Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy

Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy Michael Northcutt, Zhuqing Shi, Michael Zijlstra, Ayush Shah, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-62371/v2 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 12 Feb, 2021 Read the published version in BMC Gastroenterology → Version 2 posted 9 You are reading this latest preprint version Show more versions Abstract Background: Single nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. Methods: We randomly selected 1,769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of 1.5 were categorized as low, average and elevated risk. Results: Among 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, p <0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, p <0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, p -trend <0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, p <0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps. Conclusions: GRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies. Gastroenterology & Hepatology Colonoscopy adenomatous polyps polygenic risk score colorectal cancer screening Figures Figure 1 Figure 2 Background National guidelines recommend that, in the absence of known risk factors, patients considered to be average risk for developing colorectal cancer (CRC) should begin screening at age 50 years. [ 1–4 ] The recommendation for CRC screening with colonoscopy is based on a meaningful reduction in incidence and mortality from CRC offered by timely screening. [ 5 ] The combined gastroenterology society guidelines recognize risk factors including a family history of CRC (single first-degree relative with CRC or advanced adenoma diagnosed at age <60 years or two first-degree relatives with CRC or advanced adenomas), personal history of inflammatory bowel disease, and/or a personal or family history of a hereditary colorectal cancer syndrome. [ 6 ] For patients with any of the above risk factors, colonoscopy is initiated at an earlier age and/or with more frequent follow up exams than those patients at average risk for CRC. [ 2 ] While CRC incidence has declined steadily over the past two decades in the population aged 50 years and older, limited demographic-based risk factors currently in use inadequately predict heightened CRC risk regardless of age. Moving our screening from population-based risk to individual risk requires the incorporation of genetic predisposition. Many CRC risk-associated single-nucleotide polymorphisms (SNPs) have been identified and confirmed from genome-wide association studies. [ 7–12 , 13–17 ] Although the effect of individual SNPs is modest, there is a stronger cumulative effect. SNP-based Genetic Risk Score (GRS), an odds ratio (OR)-weighted and population-standardized polygenic risk score derived from well-established CRC risk–associated SNPs, has been consistently associated with CRC risk. [ 18–23 ] In brief, it is calculated by multiplying the per-allele OR for each SNP and normalizing the risk by the mean risk expected in the population. Such an approach has been successfully implemented for other malignancies in predicting risk for breast cancer, prostate cancer, CRC and other cancers. [ 24,25 ] Few studies to date have tested the association between GRS and screening-detected adenomatous polyps. [ 26 ] As the detection of adenomatous polyps is the primary purpose of screening colonoscopy, the aim of this study is to test the association of GRS with risk of adenomatous polyps in a study population undergoing screening colonoscopy. [ 27 ] We hypothesize that, for patients who underwent screening colonoscopy at our institution and were diagnosed with advanced adenomas and non-advanced adenomas, CRC-risk associated SNPs can be used to construct a GRS to more accurately identify an individual’s risk for developing adenomatous polyps than current screening recommendations. Methods We requested the medical record number of 200,000 patients who underwent colonoscopy between January 1, 2006 and September 5, 2018 at NorthShore University HealthSystem, a large community-based academic healthcare system in northern Illinois, involving four suburban hospitals. These subjects were screened for inclusion in the Genomic Health Initiative (GHI), a DNA biobank of the NorthShore University HealthSystem. Consistent with prior studies focused on GRS, we aimed to simulate an average risk population. [ 20 ] Thus, patients must have also met the following inclusion criteria: 1) no prior or current diagnosis of CRC, hereditary CRC syndrome, ulcerative colitis or Crohn’s disease, 2) underwent screening colonoscopy at NorthShore, 3) age >45 years old at the first screening colonoscopy, 4) self-reported Caucasian, and 5) with available genotyping data from the Affymetrix Axiom™ Biobank Plus Genotyping Array. Our study only included Caucasians due to insufficient sample size for other ancestry groups. Accordingly, 1,769 patients met the inclusion criteria and detailed clinical and demographic information from each patient’s index screening colonoscopy including age, gender, BMI, family history, indication for colonoscopy as well as colonoscopy outcomes from the first screening colonoscopy were extracted from the electronic medical record. Location, size, and histologic characteristics of polyps were recorded. Positive colonoscopy was defined as any adenomatous polyps per study protocol. Advanced adenomas were defined as adenomatous polyps greater than or equal to 1 cm in size, or with a “villous” component (tubulovillous or villous), or with foci of high grade dysplasia. The study was approved by the internal review board of NorthShore University Health System. Genotypes of 22 known CRC risk-associated SNPs were extracted from a customized Axiom™ Biobank Plus Genotyping Array ( Supplementary Table 1 ). These SNPs were identified from evidence-based review of literature and met the following criteria: 1) discovered from genome-wide association studies of CRC in Caucasian subjects, with at least 1,000 cases and 1,000 controls in the first stage; 2) confirmed in additional stages with combined P <5×10 -8 ; and 3) independent, with linkage disequilibrium (LD) measurement ( r 2 <0.2) between any pair of SNPs. [ 7–17 ] Genetic risk score (GRS), an established odds ratio (OR)-weighted and population-standardized polygenic risk score was computed for each subject based on the 22 CRC risk-associated SNPs. [ 24 ] Briefly, GRS was calculated by multiplying the per-allele OR for each SNP and normalizing the risk by the average risk expected in the population (w) where, g i stands for the genotype of SNP i for an individual (0, 1, or 2 risk alleles, respectively), OR i stands for the OR of SNP i and f i stands for the risk allele frequency of SNP i . Allelic ORs obtained from the external studies and allele frequencies in the gnomAD (Non-Finnish European [NFE] population) were used in the calculation. Because GRS is population-standardized, its mean is expected to be 1.0 and its values can be interpreted as relative risk to the general population. As such, subjects with GRS of 1.5 were categorized as low, average and elevated risk prior to analysis. Both univariable and multivariable analyses were performed. For univariable analysis, differences of quantitative variables and qualitative variables among groups were tested using T-test and Chi-square, respectively. Multivariable analyses were performed to test independent effects of predictors using logistic regression modeling. A Kaplan-Meier adenomatous polyp diagnosis-free survival analysis was used to test association between GRS and age at abnormal colonoscopy. Statistical analyses were performed by R version 3.5.2, and two-tailed P <0.05 was considered statistically significant. Results Among the 1,769 subjects included in this study, 520 subjects had one or more adenomatous polyps on their first screening colonoscopy, yielding an adenoma detection rate of 29.4% overall (24.6% for females, 37.5% for males). While male gender and higher body mass index (BMI) were significantly associated with risk of adenomatous polyps at screening colonoscopy in univariable and multivariable analysis, age was significant on only univariable analysis ( Table 1 ). The mean and 95% confidence interval (CI) age at first screening colonoscopy was 61.0 (60.3-61.6) and 60.2 (59.8-60.6) years old, respectively, in subjects with and without adenomatous polyps, OR (95%CI) = 1.01 (1.00-1.03) , p = 0.04. The mean (95% CI) BMI was 29.5 (29.0-30.0) and 28.0 (27.7-28.3), respectively, in subjects with and without adenomatous polyps [OR (95%CI) = 1.04 (1.02-1.05), p < 0.001]. The proportion of male gender was 47.5% and 32.9%, respectively in subjects with and without adenomatous polyps [OR (95%CI) = 1.84 (1.55-2.20), p < 0.001]. In contrast, positive family history was not associated with risk of having adenomatous polyps; it was found in 7.7% and 7.0% subjects with and without adenomatous polyps [OR (95%CI) = 1.11 (0.8-1.54), p = 0.7]. Table 1. Association of variables with screening colonoscopy outcomes. Univariate analysis Multivariable analysis Variables Positive 1 (N=520) Negative 2 (N=1,249) OR (95% CI) p OR (95% CI) p Age at colonoscopy, mean (95% CI) 61.0 (60.3-61.6) 60.2 (59.8-60.6) 1.01 (1-1.03) 0.04 1.01 (1-1.02) 0.1 Gender, No. (%) of male 247 (47.5) 411 (32.9) 1.84 (1.55-2.2) <0.001 1.8 (1.51-2.15) <0.001 Positive family history, No. (%) 40 (7.7) 87 (7.0) 1.11 (0.8-1.54) 0.66 1.14 (0.81-1.58) 0.53 BMI, mean (95% CI) 29.5 (28.9-30) 28.0 (27.7-28.3) 1.04 (1.02-1.05) <0.001 1.04 (1.02-1.05) <0.001 GRS, mean (95% CI) 1.02 (1-1.05) 0.97 (0.95-0.99) 1.61 (1.24-2.08) <0.001 1.63 (1.25-2.12) <0.001 1 Positive: adenomatous polyps 2 Negative: no polyps or hyperplastic polyps CI, confidence interval; OR, odds ratio; BMI, body mass index; GRS, genetic risk score ciated with increased risk of adenomatous polyps. The mean (95% CI) GRS was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, in subjects with and without adenomatous polyps [OR (95%CI) = 1.61 (1.24-2.08), p = 0.003]. This association was independent of other known predictors in a multivariable analysis; OR (95%) = 1.63 (1.25-2.12), p = 0.003 when adjusting for age, gender, BMI and family history ( Table 1 ). The detection rate of adenomatous polyps increased with higher categorical GRS risk groups, 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS risk group, respectively, p -trend < 0.001 ( Figure 1 ). A Kaplan-Meier curve analysis examining the time to the first diagnosis of adenomatous polyps over the lifespan of the patient starting at birth (time=zero) revealed that subjects in the higher GRS risk groups had an earlier age diagnosis of adenomatous polyp(s). The difference was statistically significant based on the Log rank test, p = 0.001 ( Figure 2 ). Association of GRS with detailed colonoscopy outcomes is presented in Table 2 . The mean (95% CI) of GRS was similar for subjects with different sizes of adenomatous polyps; 1.02 (0.97-1.06) and 1.03 (1.00-1.07) for those with size 0.5 cm ( p < 0.001). Likewise, the mean (95% CI) of GRS was similar for subjects with different numbers of adenomatous polyps; 1.04 (1.00-1.07) and 1.01 (0.96-1.15) for those with one or more than one adenomatous polyps, respectively. The mean GRS was also similar for adenomatous polyps at different locations (cecum/ascending colon, transverse/descending colon, or rectum/sigmoid). The association was significant in patients for polyps in the cecum/ascending colon ( p = 0.02). The mean GRS (95% CI) was 1.02 (0.97-1.08) for 126 subjects with advanced adenoma(s), but did not reach statistical significance ( p = 0.1). Table 2 . Association of GRS with detailed features of colonoscopy outcomes Variables No. subjects GRS, mean (95% CI) OR (95% CI) p No polyps or HP 1249 0.97 (0.95-0.99) 1 Adenomatous polyps 520 1.02 (1-1.05) 1.61 (1.24-2.08) <0.001 Polyp size <0.5 cm 203 1.02 (0.97-1.06) 1.49 (1.03-2.13) 0.07 Polyp size ≥0.5 cm 316 1.03 (1-1.07) 1.68 (1.23-2.27) <0.001 Advanced adenoma 126 1.02 (0.97-1.08) 1.56 (0.99-2.42) 0.10 Total No. of polyps No. =1 304 1.04 (1-1.07) 1.77 (1.3-2.41) 1 216 1.01 (0.96-1.15) 1.38 (0.96-1.96) 0.14 Location CA 296 1.02 (0.98-1.06) 1.56 (1.14-2.12) 0.02 TD 197 1.02 (0.97-1.06) 1.49 (1.02-2.14) 0.08 RS 159 1.02 (0.97-1.08) 1.57 (1.05-2.33) 0.06 GRS, genetic risk score; CI, confidence interval; OR, odds ratio; HP, hyperplastic polyp(s); BMI, body mass index; CA, cecum/ascending colon; TD, transverse/descending colon; RS, rectum and sigmoid colon Discussion In this retrospective analysis of screening colonoscopy data from 1,769 patients at a community-based, high volume healthcare system involving four hospital-based gastroenterology labs and two free-standing endoscopy units, we developed and characterized a SNP-based, odds ratio-weighted and population-standardized polygenic genetic risk score (GRS). Our results demonstrated the GRS was significantly higher for patients who had adenomatous polyps on colonoscopy compared to those who did not ( Table 1 ). Furthermore, this novel association was independent of age, gender, BMI and family history on multivariable analysis. As shown in Figure 1, the proportion of cases with adenomatous polyps trended up in patients stratified by three tertiles of GRS, which is similar to previous studies. [ 20,22 ] Based on our findings, higher GRS risk groups have an earlier diagnosis of adenomatous polyps ( Figure 2 ). Kaplan-Meier time-to-event analysis from birth (time=zero) to first screening colonoscopy identifying an adenomatous polyp(s) differed significantly among the three GRS risk groups based on the Log rank test. The time-to-event analysis is justified for germline predictors such as GRS because they can be measured at age zero. Since the probability of finding a polyp increases with age, this analysis demonstrates the predictive nature for adenomatous polyps across GRS risks at any given age. Furthermore, the predictive value of GRS for adenomatous polyps versus no adenomatous polyps was primarily driven by polyps measuring greater than or equal to 0.5 cm ( Table 2 ). For polyps >1 cm (i.e. advanced adenomas), our data shows a trend toward similar predictive value which is consistent with prior studies. [ 22 ] The lack of statistical significance is presumably related to small sample size; only 126 of the total 1769 patients had advanced adenomas in our study population. Interestingly, GRS for adenomatous polyps localized to the cecum and ascending colon was significantly higher than for patients with no adenomatous polyps on colonoscopy. These results parallel the prior study by Weigl et al , in which odds ratios were largest for proximal advanced neoplasms. [ 22 ] As our data incorporates all right sided polyps, including sessile serrated polyps, and is consistent with other studies, we believe this highlights the potential future clinical utility of GRS for risk stratification. Specifically, right sided CRC confers higher morbidity and mortality with poorer outcomes, and any strategy to identify these patients earlier would have a greater clinical impact. [ 28 ] The clinical importance of detecting and removing small nonadvanced adenomas is currently controversial. However, our data for adenomatous polyps <1 cm demonstrated that detection of these lesions may have clinical relevance by further stratifying risk for an individual in our population. It is noteworthy that the most recent guidelines have lengthened the interval to follow up colonoscopy from 5-10 years to 7-10 years in patients with one to two small adenomas <10 mm in size. [ 29 ] Our data, however, lends support to maintaining more conservative surveillance intervals in patients with nonadvanced lesions. In addition, our study confirms previously identified CRC risk factors by demonstrating male gender and higher BMI were significantly associated with risk of adenomatous polyps on multivariable analysis. Interestingly, family history was not associated with presence of adenomatous polyps. This finding reinforces the limited clinical utility of family history alone as a CRC risk factor. [ 20 ] In our medical record, as in many other healthcare systems, family history is variably recorded and often incomplete. This may be an issue of misreporting among family members as to their health-related conditions, incomplete documentation by healthcare providers, and/or the true lack of predictive power of family history. As such, this data collected by chart review adds a great deal of subjectivity. In contrast, the objective nature of genetic stratification leads to a more individualized and reproducible approach. Despite the objectivity that genetic data provides to any individual, there are inherent limitations of utilizing a SNP-based approach for risk stratification. As in other studies, our investigation used high impact, well-established risk-associated SNPs for calculation of GRS ( Supplementary Table 1 ). [ 20,22 ] GRS calculations are based on the number of SNPs tested on the chosen array which may be limited by commercial and research availability. Thus, our GRS only incorporates the known common genetic susceptibility variants for CRC that were included in the customized Axiom™ Biobank Plus Genotyping Array. It is intuitive that with further identification of SNPs associated with CRC that the predictive value of a GRS will further be improved. In contrast to other studies that tested associations of GRS with CRC risk, our study is the first one to test the association of GRS with risk of adenomatous polyps among average-risk subjects from a community-based health care system. [ ­­ 20 ] However, as a single healthcare system, our data is limited in number and scope compared to studies using large epidemiological consortia. With the lack of access to additional risk factors (i.e. physical activity, alcohol/tobacco use, and dietary factors such as low fiber and high red meat consumption) and limited numbers of patients compared to these population-based studies, it is not possible to unite genetic data with epidemiologic data to develop a truly integrated GRS. Specifically, in contrast to the study by Jeon et al which used two large population-based data consortia, we did not strive to reproduce their findings. [ 20 ] Despite these limitations, our results were similar to studies with access to such data. An additional consideration is that we included patients who had a coded indication (ICD-10 code) for screening colonoscopy. However, this may not always reflect the true indication for the procedure as stated; embedded in this population may be symptomatic patients, thus introducing a higher probability of neoplastic disease. Although not evaluated, we believe that this theoretical selection bias would minimally affect our results. Conclusions An ideal population-based CRC screening program would include a predictable and reproducible stratification schema to appropriately initiate and surveil patients. While current screening guidelines rely on demographics and epidemiologic risk factors for CRC, the availability of known or suspected risk factors, and the reproducibility of that data, may be lacking. A reasonable objective is to focus on genetic predisposition to stratify large populations of patients. With the option of genetic testing for patients becoming more accepted, and with the continued identification of additional SNPs associated with CRC, GRS can be more easily utilized for a patient at the bedside. Specifically, our GRS for detection of adenomatous colon polyps could be combined with known risk factors for CRC to support clinical decision making for an individualized approach to CRC screening. Genetic risk scoring for other malignancies, including breast, prostate and ovarian cancers, has proven to have substantial clinical utility. [ 24,25 ] Our study, along with others, initiates the possibility of refining and expanding this approach for population-based risk identification to determine optimal screening strategies. Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Availability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interests: The authors declare that they have no competing interests Funding: This study received no funding. Authors’ contributions: MN, MZ, AS, OK, JX, and JG made substantial contributions to the conception and design of the work; MN, ZS, MZ, AS, SZ, OK, MB, PI, AV, OA, JX, and JG made significant contributions to the acquisition, analysis, and/or interpretation of data; MN, EY, OK, JX, and JG have drafted the work and/or substantively revised it. All authors read and approved the final manuscript. Acknowledgements: Not applicable References Rex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. Gastrointest Endosc . 2017;86(1):18-33. doi:10.1016/j.gie.2017.04.003 Rex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American college of gastroenterology guidelines for colorectal cancer screening 2008. Am J Gastroenterol . 2009;104(3):739-750. doi:10.1038/ajg.2009.104 Bibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for colorectal cancer: US preventive services task force recommendation statement. JAMA - J Am Med Assoc . 2016;315(23):2564-2575. doi:10.1001/jama.2016.5989 Qaseem A, Crandall CJ, Mustafa RA, et al. Screening for colorectal cancer in asymptomatic average-risk adults: A guidance statement from the American College of Physicians. Ann Intern Med . 2019;171(9):643-654. doi:10.7326/M19-0642 Nishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. N Engl J Med . 2013;369(12):1095-1105. doi:10.1056/NEJMoa1301969 Kaltenbach T, Anderson JC, Burke CA, et al. Endoscopic Removal of Colorectal Lesions—Recommendations by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology . 2020;158(4):1095-1129. doi:10.1053/j.gastro.2019.12.018 Dunlop MG, Dobbins SE, Farrington SM, et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet . 2012;44(7):770-776. doi:10.1038/ng.2293 PETERS U, et. al. Tumors in a Genome-wide Meta-analysis. Gastroenterology . 2013;144(4):799-807. doi:10.1053/j.gastro.2012.12.020.Conflicts Houlston RS, Cheadle J, Dobbins SE, et al. Europe PMC Funders Group Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41 , 3q26 . 2 ,. 2016;42(11):973-977. doi:10.1038/ng.670.Meta-analysis Schmit SL, Edlund CK, Schumacher FR, et al. Novel common genetic susceptibility loci for colorectal cancer. J Natl Cancer Inst . 2019;111(2):146-157. doi:10.1093/jnci/djy099 Broderick P, Carvajal-Carmona L, Pittman AM, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet . 2007;39(11):1315-1317. doi:10.1038/ng.2007.18 Houlston RS, Webb E, Broderick P, et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet . 2008;40(12):1426-1435. doi:10.1038/ng.262 Jia W, Zhang B, Matsuo K, et al. HHS Public Access. 2013;45(2):191-196. doi:10.1038/ng.2505.Genome-wide Tenesa A, Farrington SM, Prendergast JGD, et al. NIH Public Access. 2009;40(5):631-637. doi:10.1038/ng.133.Genome-wide Tomlinson IPM, Carvajal-Carmona LG, Dobbins SE, et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet . 2011;7(6):2-12. doi:10.1371/journal.pgen.1002105 Tomlinson IPM, Webb E, Carvajal-Carmona L, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet . 2008;40(5):623-630. doi:10.1038/ng.111 Whiffin N, Hosking FJ, Farrington SM, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet . 2014;23(17):4729-4737. doi:10.1093/hmg/ddu177 Hsu L, Jeon J, Brenner H, et al. A model to determine colorectal cancer risk using common genetic susceptibility loci. Gastroenterology . 2015;148(7):1330-1339.e14. doi:10.1053/j.gastro.2015.02.010 Tung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat Rev Clin Oncol . 2016;13(9):581-588. doi:10.1038/nrclinonc.2016.90 Jeon J, Du M, Schoen RE, et al. Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. Gastroenterology . 2018;154(8):2152-2164.e19. doi:10.1053/j.gastro.2018.02.021 Archambault AN, Su YR, Jeon J, et al. Cumulative Burden of Colorectal Cancer–Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer. Gastroenterology . 2020;158(5):1274-1286.e12. doi:10.1053/j.gastro.2019.12.012 Weigl K, Thomsen H, Balavarca Y, Hellwege JN, Shrubsole MJ, Brenner H. Genetic Risk Score Is Associated With Prevalence of Advanced Neoplasms in a Colorectal Cancer Screening Population. Gastroenterology . 2018;155(1):88-98.e10. doi:10.1053/j.gastro.2018.03.030 Frampton MJE, Law P, Litchfield K, et al. Implications of polygenic risk for personalised colorectal cancer screening. Ann Oncol . 2016;27(3):429-434. doi:10.1093/annonc/mdv540 Na R, Labbate C, Yu H, et al. Single-Nucleotide Polymorphism-Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis. JAMA Netw open . 2019;2(12):e1918145. doi:10.1001/jamanetworkopen.2019.18145 Kuchenbaecker KB, McGuffog L, Barrowdale D, et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst . 2017;109(7):1-15. doi:10.1093/jnci/djw302 Zhang B, Shrubsole MJ, Li G, et al. Association of genetic variants for colorectal cancer differs by subtypes of polyps in the colorectum. Carcinogenesis . 2012;33(12):2417-2423. doi:10.1093/carcin/bgs308 Rex DK. Maximizing detection of adenomas and cancers during colonoscopy. Am J Gastroenterol . 2006;101(12):2866-2877. doi:10.1111/j.1572-0241.2006.00905.x Nakagawa-Senda H, Hori M, Matsuda T, Ito H. Prognostic impact of tumor location in colon cancer: The Monitoring of Cancer Incidence in Japan (MCIJ) project. BMC Cancer . 2019;19(1):1-9. doi:10.1186/s12885-019-5644-y Gupta S, Lieberman D, Anderson JC, et al. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. Gastroenterology . 2020;158(4):1131-1153.e5. doi:10.1053/j.gastro.2019.10.026 Supplemental Table Supplementary Table 1. Known risk-associated SNPs for colorectal cancer available from Affymetrix Axiom™ Biobank Plus Genotyping Array SNP Chromosome Position Risk allele Risk allele frequency Odds ratio Reference rs6691170 1 222045446 T 0.339787 1.06 Houlston RS.Nat Genet.2010 rs10936599 3 169492101 C 0.779708 1.08 Houlston RS.Nat Genet.2010 rs647161 5 134499092 A 0.618072 1.07 Jia WH,Nat Genet. 2013 rs16892766 8 117630683 C 0.093778 1.25 Tomlinson IP.Nat Genet.2008 rs3824999 11 74345550 G 0.395611 1.20 Whiffin N,Hum Mol Genet. 2014 rs3802842 11 111171709 C 0.297764 1.15 Tenesa A.Nat Genet.2008 rs10774214 12 4368352 T 0.459643 1.04 Jia WH,Nat Genet. 2013 rs7136702 12 50880216 T 0.408275 1.06 Houlston RS.Nat Genet.2010 rs11169552 12 51155663 C 0.749553 1.09 Houlston RS.Nat Genet.2010 rs1957636 14 54560018 T 0.516293 1.08 Tomlinson IP,PLoS Genet. 2011 rs4779584 15 32994756 T 0.341785 1.15 Tomlinson IP,PLoS Genet. 2011 rs9929218 16 68820946 G 0.72056 1.10 COGENT Study,Nat Genet.2008 rs4939827 18 46453463 T 0.353235 1.18 Broderick P,Nat Genet. 2007 rs10411210 19 33532300 C 0.795237 1.15 COGENT Study,Nat Genet.2008 rs961253 20 6404281 A 0.32519 1.12 Tomlinson IP,PLoS Genet. 2011 rs4925386 20 60921044 C 0.577073 1.08 Houlston RS.Nat Genet.2010 rs10795668 10 8701219 G 0.757007 1.12 Tomlinson IP.Nat Genet.2008 rs6687758 1 222164948 G 0.210459 1.09 Schmit SL,J Natl Cancer Inst. 2018 rs4444235 14 54410919 C 0.415885 1.08 Schmit SL,J Natl Cancer Inst. 2018 rs4813802 20 6699595 G 0.282094 1.08 Schmit SL,J Natl Cancer Inst. 2018 rs11903757 2 192587204 C 0.16506 1.16 Peters U.Gastroenterology.2012 rs5934683 X 9751474 C 0.511889 1.07 Dunlop MG.Nat Genet.2012 1: Dunlop MG, Dobbins SE, Farrington SM, et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet. 2012 May 27;44(7):770-6. 2: Peters U, Jiao S, Schumacher FR, et al. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.Gastroenterology. 2013 Apr;144(4):799-807. 3: Houlston RS, Cheadle J, Dobbins SE, et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet. 2010 Nov;42(11):973-7. 4: Schmit SL, Edlund CK, Schumacher FR, et al. Novel Common Genetic Susceptibility Loci for Colorectal Cancer. J Natl Cancer Inst. 2019 Feb 1;111(2):146-157. 5: Broderick P, Carvajal-Carmona L, Pittman AM, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007 Nov;39(11):1315-7. 6: COGENT Study, Houlston RS, Webb E, et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet. 2008 Dec;40(12):1426-35. 7: Jia WH, Zhang B, Matsuo K, et al. Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer. Nat Genet. 2013 Feb;45(2):191-6. 8: Tenesa A, Farrington SM, Prendergast JG, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet. 2008 May;40(5):631-7. 9: Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet. 2011 Jun;7(6):e1002105. 10: Tomlinson IP, Webb E, Carvajal-Carmona L, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet. 2008 May;40(5):623-30. 11: Whiffin N, Hosking FJ, Farrington SM, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet. 2014 Sep 1;23(17):4729-37. Supplementary Files SimplemarkupGRSBMCGASTRO.docx Cite Share Download PDF Status: Published Journal Publication published 12 Feb, 2021 Read the published version in BMC Gastroenterology → Version 2 posted Review # 2 received at journal 19 Jan, 2021 Editorial decision: Minor revision 19 Jan, 2021 Reviewer # 2 agreed at journal 19 Dec, 2020 Review # 1 received at journal 09 Dec, 2020 Reviewers invited by journal 18 Nov, 2020 Reviewer # 1 agreed at journal 18 Nov, 2020 Editor assigned by journal 16 Nov, 2020 Submission checks completed at journal 16 Nov, 2020 Editor invited by journal 16 Nov, 2020 You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-62371","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":5093363,"identity":"f3fa808e-82a5-4f2a-96e0-14acf9498476","order_by":0,"name":"Michael Northcutt","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA0klEQVRIiWNgGAWjYFCCA3CC8QGQ4OEjTksCkGBjZjYAaWEjziaIFjYJEJugFt3GswcfV/64I29wv/9Y5dccOxk2BuaHj27g0WJ24Fyy4ZmEZ4YbjjGz3Zbdlgx0GJuxcQ5eLWfMJBsSDicYgLRIbmMGauFhkyZaS7HktnoStTB+3HaYKC3Ghg1phw1nHks2lmbcdpwHGHIE/HLjjOHDBpvD8nyHDz78+HNbtT0/e/PDx/i0MEgcQLCZecAkPuUgwN+AYDP+IKR6FIyCUTAKRiQAAGTtSvN+VO+RAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0002-8538-9945","institution":"University of Chicago/NorthShore University Health System","correspondingAuthor":true,"prefix":"","firstName":"Michael","middleName":"","lastName":"Northcutt","suffix":""},{"id":5093364,"identity":"14bb329f-9b66-4da7-98ac-f42bcdd175cb","order_by":1,"name":"Zhuqing Shi","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Zhuqing","middleName":"","lastName":"Shi","suffix":""},{"id":5093365,"identity":"8cbf4a37-4135-4b7a-9f13-3b7460926b95","order_by":2,"name":"Michael Zijlstra","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Zijlstra","suffix":""},{"id":5093366,"identity":"3b8593dc-2c2b-4584-9585-53d37bef2a4a","order_by":3,"name":"Ayush Shah","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Ayush","middleName":"","lastName":"Shah","suffix":""},{"id":5093367,"identity":"453032cf-035b-4c4a-a9b7-67c3c40034e2","order_by":4,"name":"Siqun Zheng","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Siqun","middleName":"","lastName":"Zheng","suffix":""},{"id":5093368,"identity":"efa77a53-e089-4011-854f-47bdc7ff787d","order_by":5,"name":"Eugene Yen","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Eugene","middleName":"","lastName":"Yen","suffix":""},{"id":5093369,"identity":"df1e04dd-02f2-46c0-ad9c-7535fb6dc1aa","order_by":6,"name":"Omar Khan","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Omar","middleName":"","lastName":"Khan","suffix":""},{"id":5093370,"identity":"98826864-0da8-4b7b-80c9-93b3af533a9b","order_by":7,"name":"Mohammad Imran Beig","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Mohammad","middleName":"Imran","lastName":"Beig","suffix":""},{"id":5093371,"identity":"4d7dd9b6-dfe2-41e0-ace6-1c8a5a12b727","order_by":8,"name":"Polina Imas","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Polina","middleName":"","lastName":"Imas","suffix":""},{"id":5093372,"identity":"63c03c22-54c8-4395-b709-f031fd043ed4","order_by":9,"name":"Adam Vanderloo","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Adam","middleName":"","lastName":"Vanderloo","suffix":""},{"id":5093373,"identity":"91db7123-b2f2-4c4a-bab8-e6dd1fbcc199","order_by":10,"name":"Obaid Ansari","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Obaid","middleName":"","lastName":"Ansari","suffix":""},{"id":5093374,"identity":"b8c1092e-a362-410b-be42-5036c2fc3f47","order_by":11,"name":"Jianfeng Xu","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Jianfeng","middleName":"","lastName":"Xu","suffix":""},{"id":5093375,"identity":"5a4a9322-378e-4255-a3d4-4b411041b4b7","order_by":12,"name":"Jay Goldstein","email":"","orcid":"","institution":"NorthShore University HealthSystem","correspondingAuthor":false,"prefix":"","firstName":"Jay","middleName":"","lastName":"Goldstein","suffix":""}],"badges":[],"createdAt":"2020-08-19 12:05:07","currentVersionCode":2,"declarations":"","doi":"10.21203/rs.3.rs-62371/v2","doiUrl":"https://doi.org/10.21203/rs.3.rs-62371/v2","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12876-021-01645-4","type":"published","date":"2021-02-12T15:00:29+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":3917253,"identity":"b03f58da-13f1-4305-b2ea-a00c8bc81b18","added_by":"auto","created_at":"2020-12-01 15:07:56","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":23464,"visible":true,"origin":"","legend":"Detection rates of adenomatous polyps using GRS for 22 known risk-associated SNPs. Incidence of adenomatous polyps varies directly with increasing GRS. p-trend \u003c0.001 ","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-62371/v2/74e2ab41aaf9d355bc1b6ec7.JPG"},{"id":3917254,"identity":"c7f0fd7e-174c-4cb2-9134-14641da943b5","added_by":"auto","created_at":"2020-12-01 15:07:56","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":36580,"visible":true,"origin":"","legend":"Kaplan-Meier analysis demonstrating subjects in the higher GRS risk groups had an earlier age diagnosis of adenomatous polyp(s). p\u003c0.001","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-62371/v2/7b7c473fb5c74ea8fb36637b.JPG"},{"id":13620662,"identity":"35e5fe35-45ab-4088-a00e-eff3354d51f9","added_by":"auto","created_at":"2021-09-17 07:06:49","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":388135,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-62371/v2/8512f883-0c2d-42fb-85a4-61a046255a51.pdf"},{"id":3917252,"identity":"ea25d120-95f9-4336-85b5-adcee4a5fbf0","added_by":"auto","created_at":"2020-12-01 15:07:56","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":132741,"visible":true,"origin":"","legend":"","description":"","filename":"SimplemarkupGRSBMCGASTRO.docx","url":"https://assets-eu.researchsquare.com/files/rs-62371/v2/9d516e8e61aa4f9fa637ae86.docx"}],"financialInterests":"","formattedTitle":"Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy","fulltext":[{"header":"Background","content":"\u003cp\u003eNational guidelines recommend that, in the absence of known risk factors, patients considered to be average risk for developing colorectal cancer (CRC) should begin screening at age 50 years.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e1\u0026ndash;4\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e The recommendation for CRC screening with colonoscopy is based on a meaningful reduction in incidence and mortality from CRC offered by timely screening.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e5\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e The combined gastroenterology society guidelines recognize risk factors including a family history of CRC (single first-degree relative with CRC or advanced adenoma diagnosed at age \u0026lt;60 years or two first-degree relatives with CRC or advanced adenomas), personal history of inflammatory bowel disease, and/or a personal or family history of a hereditary colorectal cancer syndrome.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e6\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e For patients with any of the above risk factors, colonoscopy is initiated at an earlier age and/or with more frequent follow up exams than those patients at average risk for CRC.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e2\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e While CRC incidence has declined steadily over the past two decades in the population aged 50 years and older, limited demographic-based risk factors currently in use inadequately predict heightened CRC risk regardless of age.\u003c/p\u003e\n\u003cp\u003eMoving our screening from population-based risk to individual risk requires the incorporation of genetic predisposition. Many CRC risk-associated single-nucleotide polymorphisms (SNPs) have been identified and confirmed from genome-wide association studies.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e7\u0026ndash;12\u003c/sup\u003e\u003csup\u003e,\u003c/sup\u003e\u003csup\u003e13\u0026ndash;17\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Although the effect of individual SNPs is modest, there is a stronger cumulative effect. SNP-based Genetic Risk Score (GRS), an odds ratio (OR)-weighted and population-standardized polygenic risk score derived from well-established CRC risk\u0026ndash;associated SNPs, has been consistently associated with CRC risk.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e18\u0026ndash;23\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e In brief, it is calculated by multiplying the per-allele OR for each SNP and normalizing the risk by the mean risk expected in the population. Such an approach has been successfully implemented for other malignancies in predicting risk for breast cancer, prostate cancer, CRC and other cancers.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e24,25\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Few studies to date have tested the association between GRS and screening-detected adenomatous polyps.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e26\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e As the detection of adenomatous polyps is the primary purpose of screening colonoscopy, the aim of this study is to test the association of GRS with risk of adenomatous polyps in a study population undergoing screening colonoscopy.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e27\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e We hypothesize that, for patients who underwent screening colonoscopy at our institution and were diagnosed with advanced adenomas and non-advanced adenomas, CRC-risk associated SNPs can be used to construct a GRS to more accurately identify an individual\u0026rsquo;s risk for developing adenomatous polyps than current screening recommendations.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eWe requested the medical record number of 200,000 patients who underwent colonoscopy between January 1, 2006 and September 5, 2018 at NorthShore University HealthSystem, a large community-based academic healthcare system in northern Illinois, involving four suburban hospitals. These subjects were screened for inclusion in the Genomic Health Initiative (GHI), a DNA biobank of the NorthShore University HealthSystem. Consistent with prior studies focused on GRS, we aimed to simulate an average risk population.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Thus,\u003c/p\u003e\n\u003cp\u003epatients must have also met the following inclusion criteria: 1) no prior or current diagnosis of CRC, hereditary CRC syndrome, ulcerative colitis or Crohn\u0026rsquo;s disease, 2) underwent screening colonoscopy at NorthShore, 3) age \u0026gt;45 years old at the first screening colonoscopy, 4) self-reported Caucasian, and 5) with available genotyping data from the Affymetrix Axiom\u0026trade; Biobank Plus Genotyping Array. Our study only included Caucasians due to insufficient sample size for other ancestry groups. Accordingly, 1,769 patients met the inclusion criteria and detailed clinical and demographic information from each patient\u0026rsquo;s index screening colonoscopy including age, gender, BMI, family history, indication for colonoscopy as well as colonoscopy outcomes from the first screening colonoscopy were extracted from the electronic medical record. Location, size, and histologic characteristics of polyps were recorded. Positive colonoscopy was defined as any adenomatous polyps per study protocol. Advanced adenomas were defined as adenomatous polyps greater than or equal to 1 cm in size, or with a \u0026ldquo;villous\u0026rdquo; component (tubulovillous or villous), or with foci of high grade dysplasia. The study was approved by the internal review board of NorthShore University Health System.\u003c/p\u003e\n\u003cp\u003eGenotypes of 22 known CRC risk-associated SNPs were extracted from a customized Axiom\u0026trade; Biobank Plus Genotyping Array (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e). These SNPs were identified from evidence-based review of literature and met the following criteria: 1) discovered from genome-wide association studies of CRC in Caucasian subjects, with at least 1,000 cases and 1,000 controls in the first stage; 2) confirmed in additional stages with combined \u003cem\u003eP\u003c/em\u003e\u0026lt;5\u0026times;10\u003csup\u003e-8\u003c/sup\u003e; and 3) independent, with linkage disequilibrium (LD) measurement (\u003cem\u003er\u003c/em\u003e\u003csup\u003e2\u003c/sup\u003e \u0026lt;0.2) between any pair of SNPs.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e7\u0026ndash;17\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eGenetic risk score (GRS), an established odds ratio (OR)-weighted and population-standardized polygenic risk score was computed for each subject based on the 22 CRC risk-associated SNPs.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e24\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Briefly, GRS was calculated by multiplying the per-allele OR for each SNP and normalizing the risk by the average risk expected in the population (w)\u003c/p\u003e\u003cp\u003e\u003cimg src=\"https://myfiles.space/user_files/58653_1b1c6aeb34a62c68/58653_custom_files/img1606834963.jpg\"\u003e\u003c/p\u003e\u003cp\u003ewhere, \u003cem\u003eg\u003c/em\u003e\u003csub\u003ei \u003c/sub\u003estands for the genotype of SNP \u003cem\u003ei \u003c/em\u003efor an individual (0, 1, or 2 risk alleles, respectively), \u003cem\u003eOR\u003csub\u003ei\u003c/sub\u003e\u003c/em\u003e stands for the OR of SNP \u003cem\u003ei\u003c/em\u003e and \u003cem\u003ef\u003csub\u003ei\u003c/sub\u003e\u003c/em\u003e stands for the risk allele frequency of SNP \u003cem\u003ei\u003c/em\u003e. Allelic ORs obtained from the external studies and allele frequencies in the gnomAD (Non-Finnish European [NFE] population) were used in the calculation. Because GRS is population-standardized, its mean is expected to be 1.0 and its values can be interpreted as relative risk to the general population. As such, subjects with GRS of \u0026lt;0.5, 0.5-1.5 and \u0026gt;1.5 were categorized as low, average and elevated risk prior to analysis.\u003c/p\u003e\n\u003cp\u003eBoth univariable and multivariable analyses were performed. For univariable analysis, differences of quantitative variables and qualitative variables among groups were tested using T-test and Chi-square, respectively. Multivariable analyses were performed to test independent effects of predictors using logistic regression modeling. A Kaplan-Meier adenomatous polyp diagnosis-free survival analysis was used to test association between GRS and age at abnormal colonoscopy. Statistical analyses were performed by R version 3.5.2, and two-tailed \u003cem\u003eP \u003c/em\u003e\u0026lt;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eAmong the 1,769 subjects included in this study, 520 subjects had one or more adenomatous polyps on their first screening colonoscopy, yielding an adenoma detection rate of 29.4% overall (24.6% for females, 37.5% for males). While male gender and higher body mass index (BMI) were significantly associated with risk of adenomatous polyps at screening colonoscopy in univariable and multivariable analysis, age was significant on only univariable analysis (\u003cstrong\u003eTable 1\u003c/strong\u003e). The mean and 95% confidence interval (CI) age at first screening colonoscopy was 61.0 (60.3-61.6) and 60.2 (59.8-60.6) years old, respectively, in subjects with and without adenomatous polyps, OR (95%CI) = 1.01 (1.00-1.03)\u003cem\u003e, p \u003c/em\u003e= 0.04. The mean (95% CI) BMI was 29.5 (29.0-30.0) and 28.0 (27.7-28.3), respectively, in subjects with and without adenomatous polyps [OR (95%CI) = 1.04 (1.02-1.05),\u003cem\u003e p\u003c/em\u003e \u0026lt; 0.001]. The proportion of male gender was 47.5% and 32.9%, respectively in subjects with and without adenomatous polyps [OR (95%CI) = 1.84 (1.55-2.20),\u003cem\u003e p \u003c/em\u003e\u0026lt; 0.001]. In contrast, positive family history was not associated with risk of having adenomatous polyps; it was found in 7.7% and 7.0% subjects with and without adenomatous polyps [OR (95%CI) = 1.11 (0.8-1.54), \u003cem\u003ep \u003c/em\u003e= 0.7].\u003c/p\u003e\n\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:3.0pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eTable 1.\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eAssociation of variables with screening colonoscopy outcomes.\u003c/span\u003e\u003c/p\u003e\n\u003cdiv align=\"right\" style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\n \u003ctable style=\"border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" style=\"width:3.25in;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:117.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eUnivariate analysis\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width:117.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eMultivariable analysis\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eVariables\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003ePositive\u003csup\u003e1\u003c/sup\u003e (N=520)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eNegative\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e(N=1,249)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eOR (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003ep\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eOR (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003ep\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eAge at colonoscopy, mean (95% CI)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e61.0 (60.3-61.6)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e60.2 (59.8-60.6)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.01 (1-1.03)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.04\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.01 (1-1.02)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;border:none;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eGender, No. (%) of male\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e247 (47.5)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e411 (32.9)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.84 (1.55-2.2)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.8 (1.51-2.15)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003ePositive family history, No. (%)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e40 (7.7)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e87 (7.0)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.11 (0.8-1.54)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.66\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.14 (0.81-1.58)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.53\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eBMI, mean (95% CI)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e29.5 (28.9-30)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e28.0 (27.7-28.3)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.04 (1.02-1.05)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.04 (1.02-1.05)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:69.85pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eGRS, mean (95% CI)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:83.15pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.02 (1-1.05)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:81.0pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e0.97 (0.95-0.99)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:76.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.61 (1.24-2.08)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:40.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:78.4pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1.63 (1.25-2.12)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:38.6pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;text-align:center;'\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003csup\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e1\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003ePositive: adenomatous polyps\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003csup\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e2\u003c/span\u003e\u003c/sup\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eNegative: no polyps or hyperplastic polyps\u003c/span\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003cem\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eCI, confidence interval; OR, odds ratio; BMI, body mass index; GRS, genetic risk score\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\nciated with increased risk of adenomatous polyps. The mean (95% CI) GRS was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, in subjects with and without adenomatous polyps [OR (95%CI) = 1.61 (1.24-2.08),\u003cem\u003e p \u003c/em\u003e= 0.003]. This association was independent of other known predictors in a multivariable analysis; OR (95%) = 1.63 (1.25-2.12), \u003cem\u003ep \u003c/em\u003e= 0.003 when adjusting for age, gender, BMI and family history (\u003cstrong\u003eTable 1\u003c/strong\u003e). The detection rate of adenomatous polyps increased with higher categorical GRS risk groups, 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS risk group, respectively, \u003cem\u003ep\u003c/em\u003e-trend \u0026lt; 0.001 (\u003cstrong\u003eFigure 1\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eA Kaplan-Meier curve analysis examining the time to the first diagnosis of adenomatous polyps over the lifespan of the patient starting at birth (time=zero) revealed that subjects in the higher GRS risk groups had an earlier age diagnosis of adenomatous polyp(s). The difference was statistically significant based on the Log rank test, \u003cem\u003ep \u003c/em\u003e= 0.001 (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003eAssociation of GRS with detailed colonoscopy outcomes is presented in \u003cstrong\u003eTable 2\u003c/strong\u003e. The mean (95% CI) of GRS was similar for subjects with different sizes of adenomatous polyps; 1.02 (0.97-1.06) and 1.03 (1.00-1.07) for those with size \u0026lt;0.5 and \u0026sup3;0.5 cm, respectively. The association was significant in patients with adenomatous polyps \u0026gt;0.5 cm (\u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001). Likewise, the mean (95% CI) of GRS was similar for subjects with different numbers of adenomatous polyps; 1.04 (1.00-1.07) and 1.01 (0.96-1.15) for those with one or more than one adenomatous polyps, respectively. The mean GRS was also similar for adenomatous polyps at different locations (cecum/ascending colon, transverse/descending colon, or rectum/sigmoid). The association was significant in patients for polyps in the cecum/ascending colon (\u003cem\u003ep\u003c/em\u003e = 0.02). The mean GRS (95% CI) was 1.02 (0.97-1.08) for 126 subjects with advanced adenoma(s), but did not reach statistical significance (\u003cem\u003ep \u003c/em\u003e= 0.1).\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eTable 2\u003c/span\u003e\u003c/strong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e. Association of GRS with detailed features of colonoscopy outcomes\u003c/span\u003e\u003c/p\u003e\n\u003ctable style=\"border-collapse:collapse;border:none;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eVariables\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eNo. subjects\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eGRS, mean (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eOR (95% CI)\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cstrong\u003e\u003cem\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003ep\u003c/span\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eNo polyps or HP\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1249\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.97 (0.95-0.99)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;border: none;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eAdenomatous polyps\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e520\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (1-1.05)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.61 (1.24-2.08)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;Polyp size \u0026lt;0.5 cm\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e203\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (0.97-1.06)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.49 (1.03-2.13)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.07\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;Polyp size \u0026ge;0.5 cm\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e316\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.03 (1-1.07)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.68 (1.23-2.27)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eAdvanced adenoma\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e126\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (0.97-1.08)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.56 (0.99-2.42)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.10\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eTotal No. of polyps\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;No. =1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e304\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.04 (1-1.07)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.77 (1.3-2.41)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026lt;0.001\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;No. \u0026gt;1\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e216\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.01 (0.96-1.15)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.38 (0.96-1.96)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.14\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003eLocation\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;CA\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e296\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (0.98-1.06)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.56 (1.14-2.12)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.02\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;TD\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e197\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (0.97-1.06)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.49 (1.02-2.14)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.08\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 121.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e\u0026nbsp; \u0026nbsp;RS\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 67.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e159\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 112.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.02 (0.97-1.08)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 94.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e1.57 (1.05-2.33)\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 71.5pt;border-top: none;border-right: none;border-left: none;border-image: initial;border-bottom: 1pt solid windowtext;padding: 0in 5.4pt;vertical-align: top;\"\u003e\n \u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;margin-bottom:6.0pt;'\u003e\u003cspan style='font-size:15px;font-family: \"Calibri\",sans-serif;'\u003e0.06\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003cem\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eGRS, genetic risk score; CI, confidence interval; OR, odds ratio; HP, hyperplastic polyp(s); BMI, body mass index; CA, cecum/ascending colon; TD, transverse/descending colon; RS, rectum and sigmoid colon\u003c/span\u003e\u003c/em\u003e\u003c/p\u003e\n\u003cp style='margin-right:0in;margin-left:0in;font-size:16px;font-family:\"Times New Roman\",serif;margin:0in;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003e\u0026nbsp;\u003c/span\u003e\u003c/strong\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn this retrospective analysis of screening colonoscopy data from 1,769 patients at a community-based, high volume healthcare system involving four hospital-based gastroenterology labs and two free-standing endoscopy units, we developed and characterized a SNP-based, odds ratio-weighted and population-standardized polygenic genetic risk score (GRS). Our results demonstrated the GRS was significantly higher for patients who had adenomatous polyps on colonoscopy compared to those who did not (\u003cstrong\u003eTable 1\u003c/strong\u003e). Furthermore, this novel association was independent of age, gender, BMI and family history on multivariable analysis. As shown in Figure 1, the proportion of cases with adenomatous polyps trended up in patients stratified by three tertiles of GRS, which is similar to previous studies.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20,22\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eBased on our findings, higher GRS risk groups have an earlier diagnosis of adenomatous polyps (\u003cstrong\u003eFigure 2\u003c/strong\u003e). Kaplan-Meier time-to-event analysis from birth (time=zero) to first screening colonoscopy identifying an adenomatous polyp(s) differed significantly among the three GRS risk groups based on the Log rank test. The time-to-event analysis is justified for germline predictors such as GRS because they can be measured at age zero. Since the probability of finding a polyp increases with age, this analysis demonstrates the predictive nature for adenomatous polyps across GRS risks at any given age.\u003c/p\u003e\n\u003cp\u003eFurthermore, the predictive value of GRS for adenomatous polyps versus no adenomatous polyps was primarily driven by polyps measuring greater than or equal to 0.5 cm (\u003cstrong\u003eTable 2\u003c/strong\u003e). For polyps \u0026gt;1 cm (i.e. advanced adenomas), our data shows a trend toward similar predictive value which is consistent with prior studies.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e The lack of statistical significance is presumably related to small sample size; only 126 of the total 1769 patients had advanced adenomas in our study population.\u003c/p\u003e\n\u003cp\u003eInterestingly, GRS for adenomatous polyps localized to the cecum and ascending colon was significantly higher than for patients with no adenomatous polyps on colonoscopy. These results parallel the prior study by Weigl \u003cem\u003eet al\u003c/em\u003e, in which odds ratios were largest for proximal advanced neoplasms.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e22\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e As our data incorporates all right sided polyps, including sessile serrated polyps, and is consistent with other studies, we believe this highlights the potential future clinical utility of GRS for risk stratification. Specifically, right sided CRC confers higher morbidity and mortality with poorer outcomes, and any strategy to identify these patients earlier would have a greater clinical impact.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e28\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u003c/p\u003e\n\u003cp\u003eThe clinical importance of detecting and removing small nonadvanced adenomas is currently controversial. However, our data for adenomatous polyps \u0026lt;1 cm demonstrated that detection of these lesions may have clinical relevance by further stratifying risk for an individual in our population. It is noteworthy that the most recent guidelines have lengthened the interval to follow up colonoscopy from 5-10 years to 7-10 years in patients with one to two small adenomas \u0026lt;10 mm in size.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e29\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Our data, however, lends support to maintaining more conservative surveillance intervals in patients with nonadvanced lesions.\u003c/p\u003e\n\u003cp\u003eIn addition, our study confirms previously identified CRC risk factors by demonstrating male gender and higher BMI were significantly associated with risk of adenomatous polyps on multivariable analysis. Interestingly, family history was not associated with presence of adenomatous polyps. This finding reinforces the limited clinical utility of family history alone as a CRC risk factor.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e In our medical record, as in many other healthcare systems, family history is variably recorded and often incomplete. This may be an issue of misreporting among family members as to their health-related conditions, incomplete documentation by healthcare providers, and/or the true lack of predictive power of family history. As such, this data collected by chart review adds a great deal of subjectivity. In contrast, the objective nature of genetic stratification leads to a more individualized and reproducible approach.\u003c/p\u003e\n\u003cp\u003eDespite the objectivity that genetic data provides to any individual, there are inherent limitations of utilizing a SNP-based approach for risk stratification. As in other studies, our investigation used high impact, well-established risk-associated SNPs for calculation of GRS (\u003cstrong\u003eSupplementary Table 1\u003c/strong\u003e).\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20,22\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e GRS calculations are based on the number of SNPs tested on the chosen array which may be limited by commercial and research availability. Thus, our GRS only incorporates the known common genetic susceptibility variants for CRC that were included in the customized Axiom\u0026trade; Biobank Plus Genotyping Array. It is intuitive that with further identification of SNPs associated with CRC that the predictive value of a GRS will further be improved.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;In contrast to other studies that tested associations of GRS with CRC risk, our study is the first one to test the association of GRS with risk of adenomatous polyps among average-risk subjects from a community-based health care system.\u003csup\u003e[\u003c/sup\u003e\u0026shy;\u0026shy;\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e However, as a single healthcare system, our data is limited in number and scope compared to studies using large epidemiological consortia. With the lack of access to additional risk factors (i.e. physical activity, alcohol/tobacco use, and dietary factors such as low fiber and high red meat consumption) and limited numbers of patients compared to these population-based studies, it is not possible to unite genetic data with epidemiologic data to develop a truly integrated GRS. Specifically, in contrast to the study by Jeon \u003cem\u003eet al\u003c/em\u003e which used two large population-based data consortia, we did not strive to reproduce their findings.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e20\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e Despite these limitations, our results were similar to studies with access to such data.\u003c/p\u003e\n\u003cp\u003eAn additional consideration is that we included patients who had a coded indication (ICD-10 code) for screening colonoscopy. However, this may not always reflect the true indication for the procedure as stated; embedded in this population may be symptomatic patients, thus introducing a higher probability of neoplastic disease. Although not evaluated, we believe that this theoretical selection bias would minimally affect our results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eAn ideal population-based CRC screening program would include a predictable and reproducible stratification schema to appropriately initiate and surveil patients. While current screening guidelines rely on demographics and epidemiologic risk factors for CRC, the availability of known or suspected risk factors, and the reproducibility of that data, may be lacking. A reasonable objective is to focus on genetic predisposition to stratify large populations of patients. With the option of genetic testing for patients becoming more accepted, and with the continued identification of additional SNPs associated with CRC, GRS can be more easily utilized for a patient at the bedside. Specifically, our GRS for detection of adenomatous colon polyps could be combined with known risk factors for CRC to support clinical decision making for an individualized approach to CRC screening. Genetic risk scoring for other malignancies, including breast, prostate and ovarian cancers, has proven to have substantial clinical utility.\u003csup\u003e[\u003c/sup\u003e\u003csup\u003e24,25\u003c/sup\u003e\u003csup\u003e]\u003c/sup\u003e\u0026nbsp; Our study, along with others, initiates the possibility of refining and expanding this approach for population-based risk identification to determine optimal screening strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Not applicable\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interests: The authors declare that they have no competing interests\u003c/p\u003e\n\u003cp\u003eFunding: This study received no funding.\u003c/p\u003e\n\u003cp\u003eAuthors\u0026rsquo; contributions: MN, MZ, AS, OK, JX, and JG made substantial contributions to the conception\u0026nbsp;and\u0026nbsp;design of the work;\u0026nbsp;MN, ZS, MZ, AS, SZ, OK, MB, PI, AV, OA, JX, and JG made significant contributions to\u0026nbsp;the acquisition, analysis,\u0026nbsp;and/or\u0026nbsp;interpretation of data;\u0026nbsp;MN, EY, OK, JX, and JG\u0026nbsp;have drafted the work and/or substantively revised it. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003eAcknowledgements: Not applicable\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eRex DK, Boland CR, Dominitz JA, et al. Colorectal cancer screening: Recommendations for physicians and patients from the U.S. Multi-Society Task Force on Colorectal Cancer. \u003cem\u003eGastrointest Endosc\u003c/em\u003e. 2017;86(1):18-33. doi:10.1016/j.gie.2017.04.003\u003c/li\u003e\n\u003cli\u003eRex DK, Johnson DA, Anderson JC, Schoenfeld PS, Burke CA, Inadomi JM. American college of gastroenterology guidelines for colorectal cancer screening 2008. \u003cem\u003eAm J Gastroenterol\u003c/em\u003e. 2009;104(3):739-750. doi:10.1038/ajg.2009.104\u003c/li\u003e\n\u003cli\u003eBibbins-Domingo K, Grossman DC, Curry SJ, et al. Screening for colorectal cancer: US preventive services task force recommendation statement. \u003cem\u003eJAMA - J Am Med Assoc\u003c/em\u003e. 2016;315(23):2564-2575. doi:10.1001/jama.2016.5989\u003c/li\u003e\n\u003cli\u003eQaseem A, Crandall CJ, Mustafa RA, et al. Screening for colorectal cancer in asymptomatic average-risk adults: A guidance statement from the American College of Physicians. \u003cem\u003eAnn Intern Med\u003c/em\u003e. 2019;171(9):643-654. doi:10.7326/M19-0642\u003c/li\u003e\n\u003cli\u003eNishihara R, Wu K, Lochhead P, et al. Long-term colorectal-cancer incidence and mortality after lower endoscopy. \u003cem\u003eN Engl J Med\u003c/em\u003e. 2013;369(12):1095-1105. doi:10.1056/NEJMoa1301969\u003c/li\u003e\n\u003cli\u003eKaltenbach T, Anderson JC, Burke CA, et al. Endoscopic Removal of Colorectal Lesions\u0026mdash;Recommendations by the US Multi-Society Task Force on Colorectal Cancer. \u003cem\u003eGastroenterology\u003c/em\u003e. 2020;158(4):1095-1129. doi:10.1053/j.gastro.2019.12.018\u003c/li\u003e\n\u003cli\u003eDunlop MG, Dobbins SE, Farrington SM, et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. \u003cem\u003eNat Genet\u003c/em\u003e. 2012;44(7):770-776. doi:10.1038/ng.2293\u003c/li\u003e\n\u003cli\u003ePETERS U, et. al. Tumors in a Genome-wide Meta-analysis. \u003cem\u003eGastroenterology\u003c/em\u003e. 2013;144(4):799-807. doi:10.1053/j.gastro.2012.12.020.Conflicts\u003c/li\u003e\n\u003cli\u003eHoulston RS, Cheadle J, Dobbins SE, et al. Europe PMC Funders Group Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41 , 3q26 . 2 ,. 2016;42(11):973-977. doi:10.1038/ng.670.Meta-analysis\u003c/li\u003e\n\u003cli\u003eSchmit SL, Edlund CK, Schumacher FR, et al. Novel common genetic susceptibility loci for colorectal cancer. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e. 2019;111(2):146-157. doi:10.1093/jnci/djy099\u003c/li\u003e\n\u003cli\u003eBroderick P, Carvajal-Carmona L, Pittman AM, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. \u003cem\u003eNat Genet\u003c/em\u003e. 2007;39(11):1315-1317. doi:10.1038/ng.2007.18\u003c/li\u003e\n\u003cli\u003eHoulston RS, Webb E, Broderick P, et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. \u003cem\u003eNat Genet\u003c/em\u003e. 2008;40(12):1426-1435. doi:10.1038/ng.262\u003c/li\u003e\n\u003cli\u003eJia W, Zhang B, Matsuo K, et al. HHS Public Access. 2013;45(2):191-196. doi:10.1038/ng.2505.Genome-wide\u003c/li\u003e\n\u003cli\u003eTenesa A, Farrington SM, Prendergast JGD, et al. NIH Public Access. 2009;40(5):631-637. doi:10.1038/ng.133.Genome-wide\u003c/li\u003e\n\u003cli\u003eTomlinson IPM, Carvajal-Carmona LG, Dobbins SE, et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. \u003cem\u003ePLoS Genet\u003c/em\u003e. 2011;7(6):2-12. doi:10.1371/journal.pgen.1002105\u003c/li\u003e\n\u003cli\u003eTomlinson IPM, Webb E, Carvajal-Carmona L, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. \u003cem\u003eNat Genet\u003c/em\u003e. 2008;40(5):623-630. doi:10.1038/ng.111\u003c/li\u003e\n\u003cli\u003eWhiffin N, Hosking FJ, Farrington SM, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. \u003cem\u003eHum Mol Genet\u003c/em\u003e. 2014;23(17):4729-4737. doi:10.1093/hmg/ddu177\u003c/li\u003e\n\u003cli\u003eHsu L, Jeon J, Brenner H, et al. A model to determine colorectal cancer risk using common genetic susceptibility loci. \u003cem\u003eGastroenterology\u003c/em\u003e. 2015;148(7):1330-1339.e14. doi:10.1053/j.gastro.2015.02.010\u003c/li\u003e\n\u003cli\u003eTung N, Domchek SM, Stadler Z, et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. \u003cem\u003eNat Rev Clin Oncol\u003c/em\u003e. 2016;13(9):581-588. doi:10.1038/nrclinonc.2016.90\u003c/li\u003e\n\u003cli\u003eJeon J, Du M, Schoen RE, et al. Determining Risk of Colorectal Cancer and Starting Age of Screening Based on Lifestyle, Environmental, and Genetic Factors. \u003cem\u003eGastroenterology\u003c/em\u003e. 2018;154(8):2152-2164.e19. doi:10.1053/j.gastro.2018.02.021\u003c/li\u003e\n\u003cli\u003eArchambault AN, Su YR, Jeon J, et al. Cumulative Burden of Colorectal Cancer\u0026ndash;Associated Genetic Variants Is More Strongly Associated With Early-Onset vs Late-Onset Cancer. \u003cem\u003eGastroenterology\u003c/em\u003e. 2020;158(5):1274-1286.e12. doi:10.1053/j.gastro.2019.12.012\u003c/li\u003e\n\u003cli\u003eWeigl K, Thomsen H, Balavarca Y, Hellwege JN, Shrubsole MJ, Brenner H. Genetic Risk Score Is Associated With Prevalence of Advanced Neoplasms in a Colorectal Cancer Screening Population. \u003cem\u003eGastroenterology\u003c/em\u003e. 2018;155(1):88-98.e10. doi:10.1053/j.gastro.2018.03.030\u003c/li\u003e\n\u003cli\u003eFrampton MJE, Law P, Litchfield K, et al. Implications of polygenic risk for personalised colorectal cancer screening. \u003cem\u003eAnn Oncol\u003c/em\u003e. 2016;27(3):429-434. doi:10.1093/annonc/mdv540\u003c/li\u003e\n\u003cli\u003eNa R, Labbate C, Yu H, et al. Single-Nucleotide Polymorphism-Based Genetic Risk Score and Patient Age at Prostate Cancer Diagnosis. \u003cem\u003eJAMA Netw open\u003c/em\u003e. 2019;2(12):e1918145. doi:10.1001/jamanetworkopen.2019.18145\u003c/li\u003e\n\u003cli\u003eKuchenbaecker KB, McGuffog L, Barrowdale D, et al. Evaluation of polygenic risk scores for breast and ovarian cancer risk prediction in BRCA1 and BRCA2 mutation carriers. \u003cem\u003eJ Natl Cancer Inst\u003c/em\u003e. 2017;109(7):1-15. doi:10.1093/jnci/djw302\u003c/li\u003e\n\u003cli\u003eZhang B, Shrubsole MJ, Li G, et al. Association of genetic variants for colorectal cancer differs by subtypes of polyps in the colorectum. \u003cem\u003eCarcinogenesis\u003c/em\u003e. 2012;33(12):2417-2423. doi:10.1093/carcin/bgs308\u003c/li\u003e\n\u003cli\u003eRex DK. Maximizing detection of adenomas and cancers during colonoscopy. \u003cem\u003eAm J Gastroenterol\u003c/em\u003e. 2006;101(12):2866-2877. doi:10.1111/j.1572-0241.2006.00905.x\u003c/li\u003e\n\u003cli\u003eNakagawa-Senda H, Hori M, Matsuda T, Ito H. Prognostic impact of tumor location in colon cancer: The Monitoring of Cancer Incidence in Japan (MCIJ) project. \u003cem\u003eBMC Cancer\u003c/em\u003e. 2019;19(1):1-9. doi:10.1186/s12885-019-5644-y\u003c/li\u003e\n\u003cli\u003eGupta S, Lieberman D, Anderson JC, et al. Recommendations for Follow-Up After Colonoscopy and Polypectomy: A Consensus Update by the US Multi-Society Task Force on Colorectal Cancer. \u003cem\u003eGastroenterology\u003c/em\u003e. 2020;158(4):1131-1153.e5. doi:10.1053/j.gastro.2019.10.026\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Supplemental Table","content":"\u003ctable style=\"float: left;border: none;width:514.35pt;border-collapse:collapse;margin-left:6.75pt;margin-right:6.75pt;\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cstrong\u003e\u003cspan style='font-size:15px;font-family:\"Calibri\",sans-serif;'\u003eSupplementary Table 1.\u003c/span\u003e\u003c/strong\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif;\"\u003e\u0026nbsp;Known risk-associated SNPs for colorectal cancer available from Affymetrix Axiom\u0026trade;\u0026nbsp;Biobank Plus Genotyping Array\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eSNP\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eChromosome\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ePosition\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eRisk allele\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eRisk allele frequency\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eOdds ratio\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;border-top:solid windowtext 1.0pt;border-left:none;border-bottom:solid windowtext 1.0pt;border-right:none;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cstrong\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eReference\u003c/span\u003e\u003c/strong\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers6691170\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e222045446\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.339787\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.06\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eHoulston RS.Nat Genet.2010\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers10936599\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e3\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e169492101\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.779708\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.08\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eHoulston RS.Nat Genet.2010\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers647161\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e5\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e134499092\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.618072\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.07\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eJia WH,Nat Genet. 2013\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers16892766\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e8\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e117630683\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.093778\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.25\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTomlinson IP.Nat Genet.2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers3824999\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e11\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e74345550\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.395611\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.20\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eWhiffin N,Hum Mol Genet. 2014\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers3802842\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e11\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e111171709\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.297764\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.15\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTenesa A.Nat Genet.2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers10774214\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e12\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e4368352\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.459643\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.04\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eJia WH,Nat Genet. 2013\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers7136702\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e12\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e50880216\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.408275\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.06\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eHoulston RS.Nat Genet.2010\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers11169552\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e12\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e51155663\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.749553\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.09\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eHoulston RS.Nat Genet.2010\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers1957636\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e14\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e54560018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.516293\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.08\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTomlinson IP,PLoS Genet. 2011\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers4779584\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e15\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e32994756\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.341785\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.15\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTomlinson IP,PLoS Genet. 2011\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers9929218\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e16\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e68820946\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.72056\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.10\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eCOGENT Study,Nat Genet.2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers4939827\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e18\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e46453463\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eT\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.353235\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.18\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eBroderick P,Nat Genet. 2007\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers10411210\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e19\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e33532300\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.795237\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.15\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eCOGENT Study,Nat Genet.2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers961253\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e6404281\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eA\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.32519\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.12\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTomlinson IP,PLoS Genet. 2011\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers4925386\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e60921044\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.577073\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.08\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eHoulston RS.Nat Genet.2010\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers10795668\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e10\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e8701219\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.757007\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.12\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eTomlinson IP.Nat Genet.2008\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers6687758\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e222164948\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.210459\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.09\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eSchmit SL,J Natl Cancer Inst. 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers4444235\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e14\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e54410919\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.415885\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.08\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eSchmit SL,J Natl Cancer Inst. 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers4813802\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e20\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e6699595\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eG\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.282094\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.08\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eSchmit SL,J Natl Cancer Inst. 2018\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers11903757\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e2\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e192587204\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.16506\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.16\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ePeters U.Gastroenterology.2012\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003ers5934683\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.45pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eX\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:56.45pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e9751474\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:66.95pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eC\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:52.65pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e0.511889\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:42.65pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;text-align:center;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1.07\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width:148.5pt;border:none;border-bottom:solid windowtext 1.0pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003eDunlop MG.Nat Genet.2012\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width:80.7pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:66.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:56.45pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:66.95pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:52.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:42.65pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003ctd style=\"width:148.5pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cbr\u003e\u003c/span\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e1: Dunlop MG, Dobbins SE, Farrington SM, et al. Common variation near CDKN1A, POLD3 and SHROOM2 influences colorectal cancer risk. Nat Genet. 2012 May 27;44(7):770-6.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e2: Peters U, Jiao S, Schumacher FR, et al. Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis.Gastroenterology. 2013 Apr;144(4):799-807.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e3: Houlston RS, Cheadle J, Dobbins SE, et al. Meta-analysis of three genome-wide association studies identifies susceptibility loci for colorectal cancer at 1q41, 3q26.2, 12q13.13 and 20q13.33. Nat Genet. 2010 Nov;42(11):973-7.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e4: Schmit SL, Edlund CK, Schumacher FR, et al. Novel Common Genetic Susceptibility Loci for Colorectal Cancer. J Natl Cancer Inst. 2019 Feb 1;111(2):146-157.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e5: Broderick P, Carvajal-Carmona L, Pittman AM, et al. A genome-wide association study shows that common alleles of SMAD7 influence colorectal cancer risk. Nat Genet. 2007 Nov;39(11):1315-7.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e6: COGENT Study, Houlston RS, Webb E, et al. Meta-analysis of genome-wide association data identifies four new susceptibility loci for colorectal cancer. Nat Genet. 2008 Dec;40(12):1426-35.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e7: Jia WH, Zhang B, Matsuo K, et al. Genome-wide association analyses in East Asians identify new susceptibility loci for colorectal cancer. Nat Genet. 2013 Feb;45(2):191-6.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e8: Tenesa A, Farrington SM, Prendergast JG, et al. Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21. Nat Genet. 2008 May;40(5):631-7.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e9: Tomlinson IP, Carvajal-Carmona LG, Dobbins SE, et al. Multiple common susceptibility variants near BMP pathway loci GREM1, BMP4, and BMP2 explain part of the missing heritability of colorectal cancer. PLoS Genet. 2011 Jun;7(6):e1002105.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e10: Tomlinson IP, Webb E, Carvajal-Carmona L, et al. A genome-wide association study identifies colorectal cancer susceptibility loci on chromosomes 10p14 and 8q23.3. Nat Genet. 2008 May;40(5):623-30.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" style=\"width:514.35pt;padding:0in 5.4pt 0in 5.4pt;height:15.0pt;\"\u003e\n \u003cp style='margin:0in;font-size:16px;font-family:\"Times New Roman\",serif;'\u003e\u003cspan style=\"font-size: 15px;\"\u003e\u003cspan style=\"font-family: Calibri, sans-serif; color: black;\"\u003e11: Whiffin N, Hosking FJ, Farrington SM, et al. Identification of susceptibility loci for colorectal cancer in a genome-wide meta-analysis. Hum Mol Genet. 2014 Sep 1;23(17):4729-37.\u003c/span\u003e\u003c/span\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e\u003cbr\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Colonoscopy, adenomatous polyps, polygenic risk score, colorectal cancer, screening","lastPublishedDoi":"10.21203/rs.3.rs-62371/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-62371/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eSingle nucleotide polymorphism (SNP)-based polygenic risk scoring is predictive of colorectal cancer (CRC) risk. However, few studies have investigated the association of genetic risk score (GRS) with detection of adenomatous polyps at screening colonoscopy. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e We randomly selected 1,769 Caucasian subjects who underwent screening colonoscopy from the Genomic Health Initiative (GHI), a biobank of NorthShore University HealthSystem. Outcomes from initial screening colonoscopy were recorded. Twenty-two CRC risk-associated SNPs were obtained from the Affymetrix™ SNP array and used to calculate an odds ratio (OR)-weighted and population-standardized GRS. Subjects with GRS of \u0026lt;0.5, 0.5-1.5, and \u0026gt;1.5 were categorized as low, average and elevated risk.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eAmong 1,769 subjects, 520 (29%) had 1 or more adenomatous polyps. GRS was significantly higher in subjects with adenomatous polyps than those without; mean (95% confidence interval) was 1.02 (1.00-1.05) and 0.97 (0.95-0.99), respectively, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001. The association remained significant after adjusting for age, gender, body mass index, and family history, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001. The detection rate of adenomatous polyps was 10.8%, 29.0% and 39.7% in subjects with low, average and elevated GRS, respectively, \u003cem\u003ep\u003c/em\u003e-trend \u0026lt;0.001. Higher GRS was also associated with early age diagnosis of adenomatous polyps, \u003cem\u003ep\u003c/em\u003e\u0026lt;0.001. In contrast, positive family history was not associated with risk and age of adenomatous polyps.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusions: \u003c/strong\u003eGRS was significantly associated with adenomatous polyps in subjects undergoing screening colonoscopy. This result may help in stratifying average risk patients and facilitating personalized colonoscopy screening strategies.\u003c/p\u003e","manuscriptTitle":"Polygenic Risk Score is a Predictor of Adenomatous Polyps at Screening Colonoscopy","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2020-12-01 15:07:55","doi":"10.21203/rs.3.rs-62371/v2","editorialEvents":[{"type":"communityComments","content":0},{"type":"editorInvitedReview","content":"","date":"2021-01-20T00:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.\nThank you for your interesting research with good written text.\nThere are only a few concern which should be answered more than previus concerns with the other reviewers. Could you please answer them ?\n1. As I am informed, the population of Illinois is multicultural. However, you have just included Caucasians in this study. Don't you think it could be a selection bias?\n2. \"The mean and 95% confidence interval (CI) age at first screening\" Do you think that CI is meaningful regarding age of participant with and without adenoma statistically ?\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **'I declare that I have no competing interests' below**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"decision","content":"Minor revision","date":"2021-01-20T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-12-20T00:00:00+00:00","index":2,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-12-10T00:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after discretionary revisions\nForm responses:\n---\n\nComments to Author:\n---\nThank you for your kind response.\nI am satisfied with your comments.\nTo improve the quality, I suggest that you reflect your responses for my mentioned point 2 (The low GRS group seems...) and point 3 (Table 3 indicates the association...) in the manuscript.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewersInvited","content":"","date":"2020-11-19T00:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-11-19T00:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-11-17T00:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-11-16T23:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-11-16T23:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2020-09-02 16:46:13","doi":"10.21203/rs.3.rs-62371/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-10-29T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-10T12:00:00+00:00","index":3,"fulltext":"Recommendation: Accept without revision\nForm responses:\n---\n\nComments to Author:\n---\nWell done and interesting paper to read and to know about* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **'I declare that I have no competing interests' below**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-10-07T12:00:00+00:00","index":3,"fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-09-06T12:00:00+00:00","index":2,"fulltext":"Recommendation: Major revisions required\nForm responses:\n---\n\nComments to Author:\n---\nThe authors reported the association between SNPs-based GRS and adenomatous polyps at screening colonoscopy. This study is interesting, but it requires some additional information to present usefulness of GRS for the personalized colonoscopy strategies.\n1) The low and high GRS groups is quite a few compared to the intermediate group. What is the basis for this classification? Is GRS common to be divided by 0.5 or 1.5? Please also show the distribution figure of GRS in all subjects.\n2) Figure 2 shows time to detection of adenomatous polyps. Which age does it mean when subjects first underwent colonoscopy or when they subsequently underwent colonoscopy several times and polyps were first found? The low GRS group seems to be better survival than the other groups. However, if the X label expresses the first time of colonoscopy screening, is there a possibility that the lower group simply includes older people when they underwent first colonoscopy? Background characteristics of the three groups should be listed, and please state the authors' opinion, including the backgrounds.\n3) Tables 2 indicates the association between GRS and detailed features of adenomatous polyp. How do the authors consider that multiple polyps were not related to GRS although a single polyp was related?\n4) As for the description of Table 2 in lines 199-209, I propose that it is better to change comparative degree or \"significantly…\", not \"strongest\".\n5) It seems that the first half of \"Discussion\" is similar to \"Result\". At least, I think that it does not need detailed information that have been explained in \"Result\", such as odds ratio and P-value.\n6) Please do not abbreviate SNP in abstract when it first appears. In contrast, the abbreviations of GWAS and ADR do not need because it is described in manuscript only once.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-09-06T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nPlease include all comments for the authors in this box rather than uploading your report as an attachment. Please only upload as attachments annotated versions of manuscripts, graphs, supporting materials or other aspects of your report which cannot be included in a text format.\nPlease overwrite this text when adding your comments to the authors.\nDear Authors,\nThank you for your interesting topic and good writing\n1. I suggest GRS be a key word\n2. Table 1: No polyps + positive for polyps' total percent should be 100%, Should not?\n3. Table 2: hyperplastic polyp is zero?\n4. Supplementary table 1: Are there any commercial test or at least internationally acceptable tests for diagnosis of these SNPs or they are only available in research labs?\n5. The SNP measurements is not the base of this study; however, I believe that it is reasonable to explain in a few sentences as the base of this study\n6. As the most of authors are clinicians it is worth mentioning that to explain in a few sentence the clinical use of their findings\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **'I declare that I have no competing interests' below.**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **No**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-09-02T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-08-31T12:00:00+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-08-31T12:00:00+00:00","index":1,"fulltext":""},{"type":"editorAssigned","content":"","date":"2020-08-28T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-08-27T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-08-27T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-08-19T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-gastroenterology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmge","sideBox":"Learn more about [BMC Gastroenterology](http://bmcgastroenterol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bmge/default.aspx","title":"BMC Gastroenterology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"986bf13c-2987-4b09-b7be-5ee6c57d93b2","owner":[],"postedDate":"December 1st, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":418879,"name":"Gastroenterology \u0026 Hepatology"}],"tags":[],"updatedAt":"2021-02-14T15:00:44+00:00","versionOfRecord":{"articleIdentity":"rs-62371","link":"https://doi.org/10.1186/s12876-021-01645-4","journal":{"identity":"bmc-gastroenterology","isVorOnly":false,"title":"BMC Gastroenterology"},"publishedOn":"2021-02-12 15:00:29","publishedOnDateReadable":"February 12th, 2021"},"versionCreatedAt":"2020-12-01 15:07:55","video":"","vorDoi":"10.1186/s12876-021-01645-4","vorDoiUrl":"https://doi.org/10.1186/s12876-021-01645-4","workflowStages":[]},"version":"v2","identity":"rs-62371","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-62371","identity":"rs-62371","version":["v2"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}