A Phenome-Wide Association Study of Uterine Fibroids Reveals a Marked Burden of Comorbidities

A Phenome-Wide Association Study of Uterine Fibroids Reveals a Marked Burden of Comorbidities | 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 Article A Phenome-Wide Association Study of Uterine Fibroids Reveals a Marked Burden of Comorbidities Digna Velez Edwards, Elizabeth Jasper, Brian Mautz, Jacklyn Hellwege, and 6 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3998063/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 May, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version Abstract The burden of comorbidities in those with uterine fibroids compared to those without fibroids is understudied. We performed a phenome-wide association study to systematically assess the association between fibroids and other conditions. Vanderbilt University Medical Center’s Synthetic Derivative and Geisinger Health System Database, two electronic health record databases, were used for discovery and validation. Non-Hispanic Black and White females were included. Fibroid cases were identified through a previously validated algorithm. Race-stratified and cross-ancestry analyses, adjusting for age and body mass index, were performed before significant, validated results were meta-analyzed. There were 52,200 and 26,918 (9,022 and 10,232 fibroid cases) females included in discovery and validation analyses. In cross-ancestry meta-analysis, 389 conditions were associated with fibroid risk with evidence of enrichment of circulatory, dermatologic, genitourinary, musculoskeletal, and sense organ conditions. The strongest associations within and across racial groups included conditions previously associated with fibroids. Numerous novel diagnoses, including cancers in female genital organs, were tied to fibroid status. Overall, individuals with fibroids had a marked increase in comorbidities compared to those without fibroids. This novel approach to evaluate the health context of fibroids highlights the potential to understand fibroid etiology through studying common biology of comorbid diagnoses and through disease networks. Health sciences/Diseases/Reproductive disorders/Urogenital reproductive disorders Health sciences/Signs and symptoms/Comorbidities uterine fibroids leiomyoma disease burden electronic health records phenome-wide association study Figures Figure 1 Figure 2 Introduction Uterine fibroids are benign neoplasms originating in the smooth muscle of the uterus. They are the most common female pelvic tumor developing in up to 80% of females by menopause and account for up to $ 34 billion dollars in health care costs in the United States annually 1 – 4 . Fibroids are the leading indication for hysterectomy 4 . Symptomatic fibroids have a range of reproductive health effects including heavy and painful menses, anemia, pelvic pain, and pregnancy complications 5 . However, up to 50% of females remain asymptomatic, complicating research on the etiology of fibroids as asymptomatic cases can be misclassified without pelvic imaging 2 . Current understanding of the clinical risk factors of fibroids are limited to a small number of candidate risk factors identified primarily from self-reported fibroids or prospective cohorts of imaging confirmed fibroids. Self-reported Black race is the most well-established of risk factor for fibroids, with Black females having 2-fold higher odds of developing fibroids relative to White females 2 , 4 , 6 . Black females also develop more numerous and larger fibroids at younger ages 7 , 8 . Other factors associated with increased fibroid risk include higher body mass index (BMI), family history, a history of hypertension, increasing age, nulliparity, and earlier age at menarche 2 , 3 , 9 – 14 . Smoking has also been shown to be protective in some studies 13 , 15 . Phenome-wide association studies (PheWAS) offers a novel way to interrogate comorbid disease and risk relationships on a large scale. PheWAS is a data mining approach that tests for associations between an exposure (such as a genotype or a disease diagnosis) across several available disease phenotypes in a systematic, high-throughput, and reproducible way 16 , 17 . Greater access to long-term information in patient electronic health records (EHRs), combined with PheWAS approaches, will capture relationships not typically collected in traditional cohort studies. PheWAS has been used successful across several topics ranging from a study evaluating the relationship between Neanderthal genome and contemporary human phenotypes to studies evaluating the comorbidities associated with systemic lupus erythematosus and leukodystrophies 18 – 21 . PheWAS provides the opportunity to uncover novel comorbidity associations not possible in typical candidate risk factor studies and allows the assessment of level of comorbidity burden. Observed associations could then be used to prioritize risk factors for treatment and modification within and across groups. We used PheWAS to systematically investigate the clinical context of fibroids, to understand broader disease associations and explore the clinical phenome. Our hypothesis was that fibroids status would be associated with known fibroid symptoms and individuals with fibroids would demonstrate an increased burden of comorbidities. Using two large clinical cohorts, we conducted PheWAS analyses using a previously published and validated phenotyping algorithm that required image confirmation to define fibroid cases and controls 22 . This study was a two-stage design with discovery analyses performed using Vanderbilt University Medical Center’s Synthetic Derivative database and Geisinger Health Systems EHR database employed for validation of discovery results. Results Study Populations We identified over 52,200 females for discovery analyses in the SD database that had complete covariate information and were included in analyses (9,022 cases, 43,273 controls, Table 1). In the GHS validation cohort, there were 26,918 (10,232 cases, 16,686 controls) females with complete covariate information (Fig. 1 A). Non-Hispanic Black individuals made up 19.88% and 3.51% of the discovery and validation populations. Average age at diagnosis was lower in Black cases relative to White cases in both populations. Average BMI in cases was higher relative to controls in both races. In the discovery population, Black individuals had a higher proportion of individuals with hypertension and Type 2 diabetes relative to White individuals. There was a higher burden of diabetes and hypertension in both cases and controls in GHS cohort compared to the population from the SD, likely due to the generally older and higher burden of obesity of the GHS patients 23 . SD Database Discovery PheWAS In discovery analyses using the SD, a total of 1,678 and 1,743 tests were performed in Blacks and Whites, respectively Table S1 -S2). Two hundred and eight associations in Blacks and 425 in Whites were statistically significant, with 190 associations were significant in both races in the discovery dataset (Supplemental Table 1, 2). There were 17 significant unique associations in Black females and 233 significant unique associations in White females. One association (285-other anemias) was significant in both Black and White individuals but had different directions of effect. In the cross-ancestry analysis, there were 482 significant associations (Supplemental Table 3). GHS Database Validation PheWAS In validation analyses, 197 of phecodes significant in the Black discovery population were available in the Black validation population. One-hundred and sixty-nine of these codes had the same direction of effect as in the discovery population (Table S1 ). In White females, 377 of the 420 available phecodes that were significant in the discovery population had the same direction of effect in those from the GHS database (Table S1 ). Of the 437 available phecodes that were significant in the discovery cross-ancestry analysis, 392 replicated as their direction remained consistent across EHR databases (Table S3). Cross-Ancestry SD and GHS Meta-Analyses Almost all of the 392 (389, 99.23%) phecode associations that were meta-analyzed across the discovery and validation populations were significant at a Bonferroni significance level (Fig. 1 A, Tables 2, 3). Three phecodes (atherosclerosis of native arteries of the extremities with ulceration or gangrene, fracture of the foot, and open wounds of head; neck; and trunk) had suggestive significance, with p-values less than 6.23 x 10⁻⁴ but failed to reach statistical significance at the Bonferroni level. Demonstrating the strength and performance of our algorithm for defining cases and controls, the association with the largest odds ratio (OR) benign neoplasm of the uterus (OR cross = 4,625.78, 95% confidence interval [CI] = 3,507.46-6,100.66, p -value = 3.87 x 10 − 778 ). These associations were observed within individual races, in cross-ancestry meta-analyses, and across the discovery and validation cohorts (Tables 2, 4). Additionally, several known fibroid risk factors were also associated with fibroid status, including disorders of menstruation and other abnormal bleeding from female genital tract (OR cross = 6.45, 95% CI = 6.13–6.78, p -value = 5.60 x 10⁻¹¹³⁰), endometriosis (OR cross = 7.89, 95% CI = 7.02–8.88, p -value = 2.59 x 10⁻²⁵⁸), diagnoses of overweight, obesity, and other hyperalimentation (OR cross = 1.52, 95% CI = 1.45–1.60, p -value = 2.21 x 10⁻ ⁵⁸ ), disorders of lipid metabolism (OR cross = 1.47, 95% CI = 1.40–1.54, p -value = 4.61 x 10⁻⁵⁹), and vitamin D deficiency (OR cross = 1.43, 95% CI = 1.35–1.51, p -value = 4.49 x 10⁻³⁶). In addition to validating known risk factors for fibroids (Table 2), we also discovered several novel associations within the cross-ancestry meta-analyses (Table 3). Many of these novel associations were also significant within the race-stratified meta-analyses. The most significant associations within and across races and datasets were genitourinary diagnoses typically associated with fibroid symptoms (Fig. 2 A, Table 3–4) including irregular menstrual cycle (OR cross = 6.64, 95% CI = 6.31-7.00, p -value = 5.60 x 10⁻¹¹¹¹), excessive or frequent menstruation (OR cross = 12.1, 95% CI = 11.40-12.96], p -value = 1.87 x 10⁻¹²⁶²), dysmenorrhea (OR cross = 10.16, 95% CI = 9.19–11.23, p -value = 2.17 x 10⁻⁴⁴⁸), pain and other symptoms of female genital organs (OR cross = 3.02, 95% CI = 2.85–3.20, p -value = 9.09 x 10⁻³¹¹), and malaise and fatigue (OR cross = 1.42, 95% CI = 1.36–1.49, p -value = 2.02 x 10⁻⁵⁶). An array of other gynecological or reproductive diseases (Tables 2, 3) were also associated with increase odds of fibroids including endometriosis (OR cross = 7.89, 95% CI = 7.02–8.88, p -value = 2.59 x 10⁻²⁵⁸), inflammatory diseases of female pelvic organs (OR cross = 2.40, 95% CI = 2.27–2.55, p -value = 5.03 x 10⁻¹⁹⁰), noninflammatory disorders of female genitals (OR cross = 3.72, 95% CI = 3.48–3.97, p -value = 1.37 x 10⁻³³⁷), endometrial hyperplasia (OR cross = 6.94, 95% CI = 5.81–8.29, p -value = 1.76 x 10⁻¹⁰¹), and ovarian cysts (OR cross = 6.65, 95% CI = 6.21–7.12, p -value = 6.52 x 10⁻⁶³⁶). Hypotension not otherwise specified (OR cross = 0.53, 95% CI = 0.46–0.62, p -value = 4.74 x 10⁻¹⁸), a known risk factor for fibroids, was associated with a reduced risk of fibroids. Multiple other, novel circulatory system diseases and symptoms were associated with fibroids. Ischemic heart disease (OR cross = 0.66, 95% CI = 0.61–0.71, p -value = 6.84 x 10⁻²⁵), pulmonary heart disease (OR cross = 0.66, 95% CI = 0.59–0.74, p -value = 8.36 x 10⁻¹³), non-hypertensive congestive heart failure (OR cross = 0.48, 95% CI = 0.43–0.53, p -value = 2.38 x 10⁻⁴³), and peripheral vascular disease (OR cross = 0.70, 95% CI = 0.62–0.80, p -value = 2.61 x 10⁻⁷) diagnoses are also associated with reduced risk of fibroid diagnosis. Hemorrhoids (OR cross = 1.68, 95% CI = 1.54–1.84, p -value = 6.73 x 10⁻³⁰) and palpitations (OR cross = 1.55, 95% CI = 1.45–1.65, p -value = 9.66 x 10⁻³⁹) are the only two circulatory diagnoses that show increased odds (Tables 2, 3). Uterine fibroids were also associated with neoplastic growths in both genitourinary and neoplasia diagnosis categories. The association with the highest odds of fibroids, outside of benign neoplasms of the uterus under which the code for uterine fibroids fall, was malignant neoplasm of the uterus (OR cross = 247.70, 95% CI = 182.98–335.30, p -value = 9.15 x 10⁻²⁷⁹). Polyps of female genital organs (OR cross = 7.88, 95% CI = 7.04–8.82, p -value = 6.19 x 10⁻²⁸¹) was associated with increased odds of fibroids. Consistent with previous evidence of links between keloids and fibroids, we find a positive association between other hypertrophic skin conditions (phecode 701 related to scars and keloids) and uterine fibroids (OR cross = 2.02, 95% CI = 1.86–2.19, p -value = 1.13 x 10⁻⁶¹). Other benign growths such as benign neoplasms of the ovary (OR cross = 25.32, 95% CI = 20.42–31.39, p -value = 7.22 x 10⁻¹⁹¹) and mammary dysplasia (OR cross = 3.00, 95% CI = 2.76–3.27, p -value = 9.96 x 10⁻¹⁴⁵) are positively associated with uterine fibroids. Respiratory diagnoses were also significantly associated with fibroids. Most respiratory diagnoses showed increased odds of fibroids, including acute (OR cross = 2.18, 95% CI = 2.07–2.29, p -value = 5.55 x 10⁻¹⁹²) and chronic sinusitis (OR cross = 1.94, 95% CI = 1.79–2.10, p -value = 1.14 x 10⁻⁶¹), acute bronchitis and bronchiolitis (OR cross = 1.65, 95% CI = 1.54–1.76, p -value = 2.05 x 10⁻⁴⁹), and allergic rhinitis (OR cross = 1.95, 95% CI = 1.85–2.05, p -value = 3.52 x 10⁻¹⁴⁴). However, there were a few respiratory diagnoses that showed lower odds of fibroids including pleurisy, pulmonary collapse, and respiratory failure (ORs cross = 0.35–0.50, 95% CIs = 0.32–0.55 p -values < 5.00 x 10⁻³⁶). Racially Stratified Meta-Analyses All 169 phecodes that were meta-analyzed in the Black population were significantly associated with uterine fibroids after adjustment for multiple testing (Fig. 1 B). Of the 377 phecodes which were meta-analyzed in the White populations, 369 (~ 98%) were significantly associated with fibroids and only eight phecodes did not reach significance after adjusting for multiple testing (Fig. 1 C). Known risk factors, including overweight/obesity, other hypertrophic and atrophic conditions of skin, and pelvic inflammatory disease, were significantly associated with fibroids in both groups (Table 4). Symptoms often associated with fibroids, such as dysuria, pain and other symptoms associated with female genital organs, ovarian cysts, and malaise and fatigue, were also associated with fibroid diagnosis in both groups. In general, the association between fibroid status and several known and novel factors was greater in Black females relative to White females (e.g., vitamin D deficiency OR black = 2.00, 95% CI = 1.71–2.33, p -value = 7.74 x 10 ⁻¹⁹ , OR white = 1.36, 95% CI = 1.28–1.44, p -value = 1.57 x 10⁻²³; endometriosis OR black = 9.51, 95% CI = 6.91–13.08, p -value = 1.30 x 10⁻⁴³, OR white = 7.66, 95% CI = 6.75–8.70, p -value = 5.84 x 10⁻²¹⁷), though there were a few instances where the opposite was true (e.g., benign neoplasm of ovary OR black = 20.23, 95% CI = 13.04–31.38, p -value = 4.86 x 10⁻⁴¹, OR white = 27.17, 95% CI = 21.24–34.76, p -value = 5.10 x 10⁻¹⁵²). Several novel associations were observed in both Black and White populations, including genitourinary diagnoses such as genital prolapse and polyps of female genital organs (Table 4, Supplemental Table 1–2). There was an overall enrichment for positive relationships in both meta-analyses, demonstrating a marked increase in comorbidities in individuals with uterine fibroids compared to those without fibroids (Table 5). Within Black and White females and across ancestries, genitourinary diagnoses represent the highest proportion of significant replicated associations (Fig. 2 B, 2 C). Diagnoses in the circulatory, endocrine/metabolic, respiratory, neoplasm, and musculoskeletal groups followed, but exact rank varied by race. All diagnoses within the and musculoskeletal group were positively associated with fibroids, suggesting that fibroids and at least one musculoskeletal diagnosis or symptom co-occur. Both within and across races, diagnoses in the genitourinary group tended to be positively associated with fibroids (Tables 4–5), while circulatory diagnoses were associated with negatively correlated and tied to decreased odds of fibroids (Tables 4–5). Diagnoses in the dermatologic and sense organ groups were only positively associated with fibroids in White females alone (Table 5). Discussion Using a validated, multi-stage PheWAS, we found significant associations between fibroid status and multiple disease categories, with the strongest risk factors being among genitourinary, musculoskeletal, and neoplasms. Importantly, known fibroid risk factors, such as inflammatory diseases of female pelvic organs, disorders of menstruation and other abnormal bleeding from the female genital track, dysmenorrhea, hyperlipidemia, and vitamin D deficiency, were the most strongly associated diagnoses, highlighting the validity of our method. Outside these known risk factors, we also identified several novel diagnoses associated with uterine fibroids, including neoplasms and diagnoses linked to autoimmunity. In general, females with uterine fibroids had a significantly higher number of co-morbid diagnoses relative to control individuals. Across disease groups, diagnoses tended to be positively associated with fibroids within and across race groups, suggesting that fibroids are associated with increased comorbidities in many disease groups. Genitourinary diagnoses, such as symptoms related to menstruation (frequent, irregular, excessive), dysmenorrhea, pain in female genital organs, disorders of the urinary system, and early menopause, were the strongest associations. These diagnoses are the most typical symptoms frequently reported by individuals with symptomatic fibroids, further highlighting the validity of our phenotyping algorithm and PheWAS approach 24 – 27 . Our results also confirm previously identified relationships between other genitourinary diagnoses and uterine fibroids. For example, there was strong relationship between leiomyoma and endometriosis. Previous studies that have identified a positive relationship between endometriosis and fibroids, as well as evidence of a common genetic basis between the two conditions 28 – 31 . Known risk factors and related conditions, outside of genitourinary diagnoses, were also observed. For example, diagnoses related to BMI, an established risk factor for fibroids, were more common in individuals with fibroids regardless of race. These diagnoses, including obesity and disorders of lipid metabolism, are also established risk factors for leiomyoma 6 , 32 – 34 . Our models were adjusted for BMI, suggesting other pathways or nonlinear relationships with BMI between fibroids and these traits. Vitamin D deficiency was significantly associated with fibroids. Case-control studies have found lower Vitamin D levels in females with uterine fibroids 10 , 35 – 37 . Lower levels of Vitamin D have also been observed in Black females 38 . Our study found that Black individuals with Vitamin D deficiency had higher odds of fibroid diagnosis relative to White individuals. In vitro studies have identified a role of Vitamin D in reducing the expression of key genes related to extracellular matrix production in fibroid cells 39 . Diagnosis with atrophic skin conditions also increased odds of uterine fibroid diagnosis 40 , 41 . Our study identified several novel associations. Briefly, diagnoses such as inflammatory pelvic disease, non-inflammatory pelvic disease, and benign mammary dysplasia, which were not previously well-documented as associated with fibroids, were associated with increased odds of fibroids. As with leiomyomas, many of these genitourinary diagnoses are related to estrogen or hormone dysregulation (endometrial hyperplasia, endometriosis, pelvic inflammatory disease, cystic mastopathy) 42 – 49 . These findings suggest a plausible etiologic mechanism shared across genitourinary disease: hormone dysregulation 50 . Fibroids are generally considered as benign neoplasms 3 , 5 , 51 , 52 . However, our findings suggest common underlying biology of fibroids and both benign and malignant neoplasms. The second largest association, after benign neoplasms of the uterus (the parent code for fibroids), was malignant neoplasm of the uterus. Cervical cancer, cervical intraepithelial dysplasia, abnormal Papanicolaou smear of cervix uterine, cervical and genital polyps, as well as benign neoplasms of the ovary and breast were also positively associated with fibroids. If fibroids or polyps develop prior to genitourinary and reproductive malignancies, these conditions could risk factors and may be useful in screening tests. Diagnoses in the circulatory system category, such as ischemic heart disease, peripheral vascular disease, and congestive heart failure, were consistently associated with reduced odds of uterine fibroid diagnosis. Hypotension not otherwise specified was also negatively associated with fibroids, consistent with reports of high blood pressure and hypertension increasing risk of fibroids 11 , 53 , 54 . These results suggest an underlying mechanism linking biology of cardiovascular function and uterine fibroids. Estrogen, which has been associated with fibroid development, has known protective effects for cardiovascular disease 55 . Interestingly, obesity and metabolic disorders are typically associated with increased risk of vascular disease 56 – 58 . The links between leiomyoma, obesity, metabolic disease, and cardiovascular outcomes suggests more complex relationships between the physiology of these diagnoses that requires further research. We did not observe a consistent pattern of increased or decreased odds of fibroids within other disease groups. However, when comparing associations across remaining disease groups, we observed increased odds with immune/inflammation pathways. For example, respiratory diagnoses such as acute bronchiolitis, chronic and acute sinusitis, and upper respiratory infections were associated with increased odds of fibroids. Similarly, other disease groups like symptoms (cervical radiculitis, thoracic neuritis/radiculitis, cervicalgia 59 ), digestive (irritable bowel syndrome 60 ), musculoskeletal (synovitis/tenosynovitis, pain and stiffness in joint 61 ) and dermatological (dyschromia and vitiligo 62 , alopecia 63 ) diagnoses, which are linked with immune and/or inflammation, are also associated with increased odds of fibroids in our study. Inflammatory processes and dysregulation have previously been suggested to be involved in the development of uterine fibroids 64 , endometrial disorders 65 , and cardiovascular disease via metabolic syndrome 66 . In general, Black and White females showed similar patterns in associations. The race-specific associations tended to have related diagnoses that were significant in the cross-ancestry meta-analysis or in White females. For example, fluid overload is significant only in Black females, however, the related diagnosis of “disorders of fluid, electrolyte, and acid base balance” is significant in both races and meta-analysis. The disparity in associations between Black and White females suggests both genetic and non-genetic differences. However, it is also possible that such a large disparity is a result of lack of statistical power due to the smaller sample size of Black cases relative to White cases. Further research is needed to replicate these differences and uncover any racial disparities in diagnoses. PheWAS provides a unique way to test for comorbidities and patterns of disease in a systematic fashion. This method is dependent on EHR diagnostic and billing codes, the entry of which do not always correspond to true disease presence. Reliance on these codes could lead to bias due to misclassification. However, validation in two different EHR databases, where clinical practice and coding is likely to vary, lessens the probability that significant results are due to bias or chance. Furthermore, fibroid cases and controls were identified using our previously published algorithm, which was previously shown to have high performance. A stringent significance threshold by Bonferroni correction was also adopted to further reduced the chance of false associations. The successful identification of the well-known risk factors indicates the validity of these methods to detect real relationships. However, the associations identified in this study do not implicate causality. A well-controlled longitudinal study may provide more insight in the causal direction between fibroids and other diseases. We validated previously reported risk factors and identified novel diagnoses that have not been previously linked to uterine fibroids. In general, females with uterine fibroids bear a larger burden of comorbid traits across most disease-diagnosis groups. We detected novel significant associations of fibroids with malignant neoplasms in the uterus and cervix, as well decreased negative associations with cardiovascular diagnoses and positive associations with inflammation related diseases. This study provides the most detailed systematic research into fibroids and comorbidities to-date by leveraging large scale EHR databases and PheWAS methodology and demonstrates a novel approach to identifying previously uncharacterized comorbidities of uterine fibroids. Materials and Methods Study Populations. We utilized Vanderbilt University Medical Center’s (VUMC) Synthetic Derivative (SD) for our discovery analyses. The SD is a de-identified mirror of the VUMC EHRs containing longitudinal data, including demographic and clinical information, for over 3 million subjects who have received care in the VUMC healthcare system 67 . Non-Hispanic Black and White females 18 years or older were eligible for inclusion, with race and ethnicity defined via self-reported or by providers. Cases and controls were identified using our previously published algorithm, which has been shown to have positive and negative predictive values of 96% and 98% respectively 22 . Briefly, cases had at least one International Classification of Diseases, 9th Revision (ICD-9) or current procedure terminology (CPT) code for pelvic imaging and had at least one ICD-9 or CPT code indicating a fibroid diagnosis. Controls had at least two procedural codes for pelvic imaging without a fibroid diagnosis at time of last pelvic exam, as well as no history of hysterectomy, myomectomy, or uterine artery embolization. The Geisinger Health System (GHS) Database was used as a validation cohort, with cases and controls identified by the algorithm described above. GHS is a fully integrated health system serving three million residents of north-central and northeastern Pennsylvania. The database comes from GHS’s physician group practices which includes a network of 1,000 physicians across 75 sites, inclusive of 41 community care clinics. Statistical Analyses. PheWAS, adjusted for age and BMI, were performed with uterine fibroids as the outcome and each diagnosis, condition, or clinical characteristic (phecode) as an exposure. Analyses were performed using the PheWAS package (v 0.99.5-3) in R 68 . Discovery PheWAS was first performed in the SD before significant results were validated in GHS cohort (Fig. 1 A). A Bonferroni correction based on the number of tests in discovery population was used to determine significance ( p -value ≤ 2.98 x 10⁻⁵ for Black individuals, 2.87 x 10⁻⁵ for White individuals, 2.99 x 10⁻⁵ for cross-ancestry). Phecodes from significant associations in the discovery population were then carried forward through testing in the validation population. Inverse-variance weighted fixed-effects meta-analyses was performed, using METAL software, for associations that were significant in the discovery population and had the same direction of effect in both the discovery and validation analyses 69 . Race-stratified and cross-ancestry meta-analyses were performed across the cohorts. Bonferroni p-values for the meta-analyses were based on the number of significant phecodes in the discovery populations that were available and in the same direction in the validation populations (Black: 2.55 x 10⁻⁴; White: 1.33 x 10⁻⁴, Cross-ancestry 1.28 x 10⁻⁴). Secondary analyses, adjusting for only age, were also performed (Supplemental Table 4). Using previously described methods, phecodes were classified into 16 disease groups based largely off of organ systems and/or biologic processes 17 . A binomial test was used to test for directional relationships of significant associations across all tests, as well as to test for directional relationships within disease categories within stratified meta-analyses and cross-ancestry meta-analysis. A Bonferroni correction was used to determine significance in tests within disease categories. Declarations Competing Interests The authors report no conflict of interest. Author Contributions E.A.J. and B.S.M. conceptualized and designed the study, performed analyses, interpreted the results, and prepared the initial article, and reviewed and revised the manuscript. J.N.H. and J.A.P. contributed to the design of the study, analyses, interpretation, and preparation of the manuscript. Y.Z. performed analyses and revised the manuscript. S.H.J., S.A.P., and M.L.M., reviewed and substantially revised the manuscript. E.S.T. aided in data acquisition and revised the manuscript. T.L.E. and D.R.V.E. conceptualized and designed the study, coordinated, and supervised data acquisition and storage, made substantial contributions to the interpretation of results, and critically revised the manuscript. All authors approved the final article as submitted and agree to be accountable for all aspects of the work. Acknowledgements D.R.V.E. was supported by National Institute of Health grants R01HD074711, R01HD093671, and R03HD078567. T.E. was supported by The Vanderbilt Clinical and Translational Research Scholar Award 5KL2-RR024977 from the National Center for Advancing Translational Sciences. B.S.M was supported by National Cancer Institute grant T32 CA160056. E.A.J. and J.N.H. were supported by the NIH Building Interdisciplinary Research Career's in Women's Health career development program (K12HD043483 PIs: K.E. Hartmann, A.S. Major, and D.R.V.E.). Data Availability Statement Data for this manuscript cannot be made readily available but is readily available through IRB approval to either Vanderbilt University Medical Center or Geisinger Health System employees. References Cardozo, E. R. et al. The estimated annual cost of uterine leiomyomata in the United States. American Journal of Obstetrics and Gynecology 206 , 211.e211-211.e219, doi:10.1016/j.ajog.2011.12.002 (2012). Baird, D. 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Tables Tables 1-5 are available in the Supplementary Files section. Additional Declarations There is NO Competing Interest. Supplementary Files Table1.Demographicsofstudypopulations.xlsx Table2.Crossancestryassociationsofknownsymptomsanddiagnoseswithoddsofuterinefibroiddiagnosis.xlsx Table3.Selectcrossancestryassociationsofnovelsymptomsanddiagnoseswithincreasedanddecreasedoddsofdevelopinguterinefibroids.xlsx Table4.Selectassociationsofsymptomsanddiagnoseswithincreasedanddecreasedoddsofdevelopinguterinefibroids.xlsx Table5.Signtestsfordirectionalitywithinandacrossdiseasegroups.xlsx SupplementalTablesUFPheWASFinalNC.xlsx Cite Share Download PDF Status: Published Journal Publication published 15 May, 2025 Read the published version in Communications Medicine → Version 1 posted You are reading this latest preprint version 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. 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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-3998063","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":276608646,"identity":"235a443f-60d8-49da-af0c-001d128c96a3","order_by":0,"name":"Digna Velez Edwards","email":"data:image/png;base64,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","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":true,"prefix":"","firstName":"Digna","middleName":"Velez","lastName":"Edwards","suffix":""},{"id":276608647,"identity":"ca6464ec-3cab-4504-8fb3-cdab68458849","order_by":1,"name":"Elizabeth Jasper","email":"","orcid":"","institution":"Vanderbilt Unviersity Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Elizabeth","middleName":"","lastName":"Jasper","suffix":""},{"id":276608648,"identity":"de97387f-7b63-4460-8265-8af5f1b98d2d","order_by":2,"name":"Brian Mautz","email":"","orcid":"https://orcid.org/0000-0003-3870-2932","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Brian","middleName":"","lastName":"Mautz","suffix":""},{"id":276608649,"identity":"d5fc80cc-dc45-4b43-b877-96ed243b946c","order_by":3,"name":"Jacklyn Hellwege","email":"","orcid":"https://orcid.org/0000-0001-7479-0920","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Jacklyn","middleName":"","lastName":"Hellwege","suffix":""},{"id":276608650,"identity":"3d8eae20-81cb-4f14-9bb9-f2db0ead1df1","order_by":4,"name":"Jacqueline Piekos","email":"","orcid":"","institution":"Vanderbilt University","correspondingAuthor":false,"prefix":"","firstName":"Jacqueline","middleName":"","lastName":"Piekos","suffix":""},{"id":276608651,"identity":"dd7012d4-eef1-48e6-b025-8e36a9140a8f","order_by":5,"name":"Sarah Jones","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Jones","suffix":""},{"id":276608652,"identity":"4788b5d1-61a1-4231-b688-8f3b8120a5c0","order_by":6,"name":"Yanfei Zhang","email":"","orcid":"","institution":"Geisinger Health System","correspondingAuthor":false,"prefix":"","firstName":"Yanfei","middleName":"","lastName":"Zhang","suffix":""},{"id":276608653,"identity":"dbac2c8f-ba7a-4227-aed5-75f96be28e75","order_by":7,"name":"Eric Torstenson","email":"","orcid":"","institution":"Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Eric","middleName":"","lastName":"Torstenson","suffix":""},{"id":276608654,"identity":"704322b1-97bd-46f4-aeb6-2464d3de5ea7","order_by":8,"name":"Sarah Pendergrass","email":"","orcid":"","institution":"Geisinger Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Sarah","middleName":"","lastName":"Pendergrass","suffix":""},{"id":276608655,"identity":"31491b46-4db5-4cd8-b3a3-c248b3d576f0","order_by":9,"name":"Todd L Edwards","email":"","orcid":"","institution":"Division of Epidemiology, Department of Medicine, Vanderbilt Genetics Institute, Vanderbilt University Medical Center","correspondingAuthor":false,"prefix":"","firstName":"Todd","middleName":"L","lastName":"Edwards","suffix":""}],"badges":[],"createdAt":"2024-02-29 00:15:19","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3998063/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3998063/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s43856-025-00884-w","type":"published","date":"2025-05-15T04:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":52708820,"identity":"e07bc5f7-0f2c-4618-bfc0-f7f3b649110e","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":810238,"visible":true,"origin":"","legend":"\u003cp\u003ePheWAS study scheme and results from Discovery analysis. Manhattan plots of PheWAS outcome for final meta-analyses for cross-ancestry (A), Black (B), and White (C) populations.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/08619b411b437c0507428e89.png"},{"id":52710343,"identity":"4b9a6a2c-caaa-4519-ba2a-b66786ca73ca","added_by":"auto","created_at":"2024-03-14 19:51:10","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":794513,"visible":true,"origin":"","legend":"\u003cp\u003eBreakdown of significant, replicated PheWAS outcomes by diagnosis group for cross-ancestry (A), Black (B), and White (C) meta-analyses.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/4a2f0f03ae49746268b04776.png"},{"id":82862560,"identity":"b24f6104-2438-42cf-b577-6b98f3a6d32e","added_by":"auto","created_at":"2025-05-16 07:10:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2322377,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/f4efb4fc-006d-4fad-af7e-e3f15b5cbfee.pdf"},{"id":52708823,"identity":"81366580-5182-4e26-88a8-e85ccd082813","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":13170,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cbr\u003e\u003c/p\u003e","description":"","filename":"Table1.Demographicsofstudypopulations.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/ff984374db24d23fb8e0712c.xlsx"},{"id":52708822,"identity":"840dcdec-41db-47d9-b0bb-5f09b9f2faea","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":16039,"visible":true,"origin":"","legend":"","description":"","filename":"Table2.Crossancestryassociationsofknownsymptomsanddiagnoseswithoddsofuterinefibroiddiagnosis.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/2e2b09be56355df35de88fd9.xlsx"},{"id":52708824,"identity":"05dc8bd1-4022-4ca8-92db-4f9d61654922","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":21932,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.Selectcrossancestryassociationsofnovelsymptomsanddiagnoseswithincreasedanddecreasedoddsofdevelopinguterinefibroids.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/5fd19c70a3c429faadda6ed9.xlsx"},{"id":52708825,"identity":"009280a5-3d3d-4b16-9fa6-c3e89ceab7a6","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"xlsx","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":16942,"visible":true,"origin":"","legend":"","description":"","filename":"Table4.Selectassociationsofsymptomsanddiagnoseswithincreasedanddecreasedoddsofdevelopinguterinefibroids.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/9c1d2ebc6d9de2cdf6af7e17.xlsx"},{"id":52708827,"identity":"63f236f4-be51-49c3-9343-80d8d112d533","added_by":"auto","created_at":"2024-03-14 19:43:11","extension":"xlsx","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":13594,"visible":true,"origin":"","legend":"","description":"","filename":"Table5.Signtestsfordirectionalitywithinandacrossdiseasegroups.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/723542b16a4b81dc58774b36.xlsx"},{"id":52708826,"identity":"b80ea9f1-30ad-4876-814a-7b169695040b","added_by":"auto","created_at":"2024-03-14 19:43:10","extension":"xlsx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":1001878,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementalTablesUFPheWASFinalNC.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-3998063/v1/16a548257eb6c4fd029dc52d.xlsx"}],"financialInterests":"There is \u003cb\u003eNO\u003c/b\u003e Competing Interest.","formattedTitle":"A Phenome-Wide Association Study of Uterine Fibroids Reveals a Marked Burden of Comorbidities","fulltext":[{"header":"Introduction","content":"\u003cp\u003eUterine fibroids are benign neoplasms originating in the smooth muscle of the uterus. They are the most common female pelvic tumor developing in up to 80% of females by menopause and account for up to \u003cspan\u003e$\u003c/span\u003e34\u0026nbsp;billion dollars in health care costs in the United States annually \u003csup\u003e \u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e \u003c/sup\u003e. Fibroids are the leading indication for hysterectomy \u003csup\u003e \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e \u003c/sup\u003e. Symptomatic fibroids have a range of reproductive health effects including heavy and painful menses, anemia, pelvic pain, and pregnancy complications \u003csup\u003e \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e \u003c/sup\u003e. However, up to 50% of females remain asymptomatic, complicating research on the etiology of fibroids as asymptomatic cases can be misclassified without pelvic imaging \u003csup\u003e \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e \u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eCurrent understanding of the clinical risk factors of fibroids are limited to a small number of candidate risk factors identified primarily from self-reported fibroids or prospective cohorts of imaging confirmed fibroids. Self-reported Black race is the most well-established of risk factor for fibroids, with Black females having 2-fold higher odds of developing fibroids relative to White females \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Black females also develop more numerous and larger fibroids at younger ages \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Other factors associated with increased fibroid risk include higher body mass index (BMI), family history, a history of hypertension, increasing age, nulliparity, and earlier age at menarche \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e,\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan additionalcitationids=\"CR10 CR11 CR12 CR13\" citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Smoking has also been shown to be protective in some studies \u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePhenome-wide association studies (PheWAS) offers a novel way to interrogate comorbid disease and risk relationships on a large scale. PheWAS is a data mining approach that tests for associations between an exposure (such as a genotype or a disease diagnosis) across several available disease phenotypes in a systematic, high-throughput, and reproducible way \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e,\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. Greater access to long-term information in patient electronic health records (EHRs), combined with PheWAS approaches, will capture relationships not typically collected in traditional cohort studies. PheWAS has been used successful across several topics ranging from a study evaluating the relationship between Neanderthal genome and contemporary human phenotypes to studies evaluating the comorbidities associated with systemic lupus erythematosus and leukodystrophies \u003csup\u003e\u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. PheWAS provides the opportunity to uncover novel comorbidity associations not possible in typical candidate risk factor studies and allows the assessment of level of comorbidity burden. Observed associations could then be used to prioritize risk factors for treatment and modification within and across groups.\u003c/p\u003e \u003cp\u003eWe used PheWAS to systematically investigate the clinical context of fibroids, to understand broader disease associations and explore the clinical phenome. Our hypothesis was that fibroids status would be associated with known fibroid symptoms and individuals with fibroids would demonstrate an increased burden of comorbidities. Using two large clinical cohorts, we conducted PheWAS analyses using a previously published and validated phenotyping algorithm that required image confirmation to define fibroid cases and controls \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. This study was a two-stage design with discovery analyses performed using Vanderbilt University Medical Center\u0026rsquo;s Synthetic Derivative database and Geisinger Health Systems EHR database employed for validation of discovery results.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy Populations\u003c/h2\u003e \u003cp\u003eWe identified over 52,200 females for discovery analyses in the SD database that had complete covariate information and were included in analyses (9,022 cases, 43,273 controls, Table\u0026nbsp;1). In the GHS validation cohort, there were 26,918 (10,232 cases, 16,686 controls) females with complete covariate information (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). Non-Hispanic Black individuals made up 19.88% and 3.51% of the discovery and validation populations. Average age at diagnosis was lower in Black cases relative to White cases in both populations. Average BMI in cases was higher relative to controls in both races. In the discovery population, Black individuals had a higher proportion of individuals with hypertension and Type 2 diabetes relative to White individuals. There was a higher burden of diabetes and hypertension in both cases and controls in GHS cohort compared to the population from the SD, likely due to the generally older and higher burden of obesity of the GHS patients \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eSD Database Discovery PheWAS\u003c/h2\u003e \u003cp\u003eIn discovery analyses using the SD, a total of 1,678 and 1,743 tests were performed in Blacks and Whites, respectively Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e-S2). Two hundred and eight associations in Blacks and 425 in Whites were statistically significant, with 190 associations were significant in both races in the discovery dataset (Supplemental Table\u0026nbsp;1, 2). There were 17 significant unique associations in Black females and 233 significant unique associations in White females. One association (285-other anemias) was significant in both Black and White individuals but had different directions of effect. In the cross-ancestry analysis, there were 482 significant associations (Supplemental Table\u0026nbsp;3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eGHS Database Validation PheWAS\u003c/h2\u003e \u003cp\u003eIn validation analyses, 197 of phecodes significant in the Black discovery population were available in the Black validation population. One-hundred and sixty-nine of these codes had the same direction of effect as in the discovery population (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). In White females, 377 of the 420 available phecodes that were significant in the discovery population had the same direction of effect in those from the GHS database (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e). Of the 437 available phecodes that were significant in the discovery cross-ancestry analysis, 392 replicated as their direction remained consistent across EHR databases (Table S3).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eCross-Ancestry SD and GHS Meta-Analyses\u003c/h2\u003e \u003cp\u003eAlmost all of the 392 (389, 99.23%) phecode associations that were meta-analyzed across the discovery and validation populations were significant at a Bonferroni significance level (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA, Tables\u0026nbsp;2, 3). Three phecodes (atherosclerosis of native arteries of the extremities with ulceration or gangrene, fracture of the foot, and open wounds of head; neck; and trunk) had suggestive significance, with p-values less than 6.23 x 10⁻⁴ but failed to reach statistical significance at the Bonferroni level. Demonstrating the strength and performance of our algorithm for defining cases and controls, the association with the largest odds ratio (OR) benign neoplasm of the uterus (OR\u003csub\u003ecross\u003c/sub\u003e = 4,625.78, 95% confidence interval [CI]\u0026thinsp;=\u0026thinsp;3,507.46-6,100.66, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;3.87 x 10\u003csup\u003e\u0026minus;\u0026thinsp;778\u003c/sup\u003e). These associations were observed within individual races, in cross-ancestry meta-analyses, and across the discovery and validation cohorts (Tables\u0026nbsp;2, 4). Additionally, several known fibroid risk factors were also associated with fibroid status, including disorders of menstruation and other abnormal bleeding from female genital tract (OR\u003csub\u003ecross\u003c/sub\u003e = 6.45, 95% CI\u0026thinsp;=\u0026thinsp;6.13\u0026ndash;6.78, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.60 x 10⁻\u0026sup1;\u0026sup1;\u0026sup3;⁰), endometriosis (OR\u003csub\u003ecross\u003c/sub\u003e = 7.89, 95% CI\u0026thinsp;=\u0026thinsp;7.02\u0026ndash;8.88, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.59 x 10⁻\u0026sup2;⁵⁸), diagnoses of overweight, obesity, and other hyperalimentation (OR\u003csub\u003ecross\u003c/sub\u003e = 1.52, 95% CI\u0026thinsp;=\u0026thinsp;1.45\u0026ndash;1.60, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.21 x 10⁻\u003csup\u003e⁵⁸\u003c/sup\u003e), disorders of lipid metabolism (OR\u003csub\u003ecross\u003c/sub\u003e = 1.47, 95% CI\u0026thinsp;=\u0026thinsp;1.40\u0026ndash;1.54, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;4.61 x 10⁻⁵⁹), and vitamin D deficiency (OR\u003csub\u003ecross\u003c/sub\u003e = 1.43, 95% CI\u0026thinsp;=\u0026thinsp;1.35\u0026ndash;1.51, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;4.49 x 10⁻\u0026sup3;⁶). In addition to validating known risk factors for fibroids (Table\u0026nbsp;2), we also discovered several novel associations within the cross-ancestry meta-analyses (Table\u0026nbsp;3). Many of these novel associations were also significant within the race-stratified meta-analyses.\u003c/p\u003e \u003cp\u003eThe most significant associations within and across races and datasets were genitourinary diagnoses typically associated with fibroid symptoms (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA, Table\u0026nbsp;3\u0026ndash;4) including irregular menstrual cycle (OR\u003csub\u003ecross\u003c/sub\u003e= 6.64, 95% CI\u0026thinsp;=\u0026thinsp;6.31-7.00, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.60 x 10⁻\u0026sup1;\u0026sup1;\u0026sup1;\u0026sup1;), excessive or frequent menstruation (OR\u003csub\u003ecross\u003c/sub\u003e= 12.1, 95% CI\u0026thinsp;=\u0026thinsp;11.40-12.96], \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.87 x 10⁻\u0026sup1;\u0026sup2;⁶\u0026sup2;), dysmenorrhea (OR\u003csub\u003ecross\u003c/sub\u003e= 10.16, 95% CI\u0026thinsp;=\u0026thinsp;9.19\u0026ndash;11.23, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.17 x 10⁻⁴⁴⁸), pain and other symptoms of female genital organs (OR\u003csub\u003ecross\u003c/sub\u003e= 3.02, 95% CI\u0026thinsp;=\u0026thinsp;2.85\u0026ndash;3.20, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;9.09 x 10⁻\u0026sup3;\u0026sup1;\u0026sup1;), and malaise and fatigue (OR\u003csub\u003ecross\u003c/sub\u003e= 1.42, 95% CI\u0026thinsp;=\u0026thinsp;1.36\u0026ndash;1.49, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.02 x 10⁻⁵⁶). An array of other gynecological or reproductive diseases (Tables\u0026nbsp;2, 3) were also associated with increase odds of fibroids including endometriosis (OR\u003csub\u003ecross\u003c/sub\u003e= 7.89, 95% CI\u0026thinsp;=\u0026thinsp;7.02\u0026ndash;8.88, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.59 x 10⁻\u0026sup2;⁵⁸), inflammatory diseases of female pelvic organs (OR\u003csub\u003ecross\u003c/sub\u003e= 2.40, 95% CI\u0026thinsp;=\u0026thinsp;2.27\u0026ndash;2.55, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.03 x 10⁻\u0026sup1;⁹⁰), noninflammatory disorders of female genitals (OR\u003csub\u003ecross\u003c/sub\u003e= 3.72, 95% CI\u0026thinsp;=\u0026thinsp;3.48\u0026ndash;3.97, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.37 x 10⁻\u0026sup3;\u0026sup3;⁷), endometrial hyperplasia (OR\u003csub\u003ecross\u003c/sub\u003e= 6.94, 95% CI\u0026thinsp;=\u0026thinsp;5.81\u0026ndash;8.29, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.76 x 10⁻\u0026sup1;⁰\u0026sup1;), and ovarian cysts (OR\u003csub\u003ecross\u003c/sub\u003e= 6.65, 95% CI\u0026thinsp;=\u0026thinsp;6.21\u0026ndash;7.12, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;6.52 x 10⁻⁶\u0026sup3;⁶).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eHypotension not otherwise specified (OR\u003csub\u003ecross\u003c/sub\u003e= 0.53, 95% CI\u0026thinsp;=\u0026thinsp;0.46\u0026ndash;0.62, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;4.74 x 10⁻\u0026sup1;⁸), a known risk factor for fibroids, was associated with a reduced risk of fibroids. Multiple other, novel circulatory system diseases and symptoms were associated with fibroids. Ischemic heart disease (OR\u003csub\u003ecross\u003c/sub\u003e = 0.66, 95% CI\u0026thinsp;=\u0026thinsp;0.61\u0026ndash;0.71, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;6.84 x 10⁻\u0026sup2;⁵), pulmonary heart disease (OR\u003csub\u003ecross\u003c/sub\u003e = 0.66, 95% CI\u0026thinsp;=\u0026thinsp;0.59\u0026ndash;0.74, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;8.36 x 10⁻\u0026sup1;\u0026sup3;), non-hypertensive congestive heart failure (OR\u003csub\u003ecross\u003c/sub\u003e = 0.48, 95% CI\u0026thinsp;=\u0026thinsp;0.43\u0026ndash;0.53, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.38 x 10⁻⁴\u0026sup3;), and peripheral vascular disease (OR\u003csub\u003ecross\u003c/sub\u003e = 0.70, 95% CI\u0026thinsp;=\u0026thinsp;0.62\u0026ndash;0.80, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.61 x 10⁻⁷) diagnoses are also associated with reduced risk of fibroid diagnosis. Hemorrhoids (OR\u003csub\u003ecross\u003c/sub\u003e = 1.68, 95% CI\u0026thinsp;=\u0026thinsp;1.54\u0026ndash;1.84, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;6.73 x 10⁻\u0026sup3;⁰) and palpitations (OR\u003csub\u003ecross\u003c/sub\u003e = 1.55, 95% CI\u0026thinsp;=\u0026thinsp;1.45\u0026ndash;1.65, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;9.66 x 10⁻\u0026sup3;⁹) are the only two circulatory diagnoses that show increased odds (Tables\u0026nbsp;2, 3).\u003c/p\u003e \u003cp\u003eUterine fibroids were also associated with neoplastic growths in both genitourinary and neoplasia diagnosis categories. The association with the highest odds of fibroids, outside of benign neoplasms of the uterus under which the code for uterine fibroids fall, was malignant neoplasm of the uterus (OR\u003csub\u003ecross\u003c/sub\u003e = 247.70, 95% CI\u0026thinsp;=\u0026thinsp;182.98\u0026ndash;335.30, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;9.15 x 10⁻\u0026sup2;⁷⁹). Polyps of female genital organs (OR\u003csub\u003ecross\u003c/sub\u003e = 7.88, 95% CI\u0026thinsp;=\u0026thinsp;7.04\u0026ndash;8.82, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;6.19 x 10⁻\u0026sup2;⁸\u0026sup1;) was associated with increased odds of fibroids. Consistent with previous evidence of links between keloids and fibroids, we find a positive association between other hypertrophic skin conditions (phecode 701 related to scars and keloids) and uterine fibroids (OR\u003csub\u003ecross\u003c/sub\u003e = 2.02, 95% CI\u0026thinsp;=\u0026thinsp;1.86\u0026ndash;2.19, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.13 x 10⁻⁶\u0026sup1;). Other benign growths such as benign neoplasms of the ovary (OR\u003csub\u003ecross\u003c/sub\u003e = 25.32, 95% CI\u0026thinsp;=\u0026thinsp;20.42\u0026ndash;31.39, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;7.22 x 10⁻\u0026sup1;⁹\u0026sup1;) and mammary dysplasia (OR\u003csub\u003ecross\u003c/sub\u003e = 3.00, 95% CI\u0026thinsp;=\u0026thinsp;2.76\u0026ndash;3.27, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;9.96 x 10⁻\u0026sup1;⁴⁵) are positively associated with uterine fibroids.\u003c/p\u003e \u003cp\u003eRespiratory diagnoses were also significantly associated with fibroids. Most respiratory diagnoses showed increased odds of fibroids, including acute (OR\u003csub\u003ecross\u003c/sub\u003e = 2.18, 95% CI\u0026thinsp;=\u0026thinsp;2.07\u0026ndash;2.29, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.55 x 10⁻\u0026sup1;⁹\u0026sup2;) and chronic sinusitis (OR\u003csub\u003ecross\u003c/sub\u003e = 1.94, 95% CI\u0026thinsp;=\u0026thinsp;1.79\u0026ndash;2.10, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.14 x 10⁻⁶\u0026sup1;), acute bronchitis and bronchiolitis (OR\u003csub\u003ecross\u003c/sub\u003e = 1.65, 95% CI\u0026thinsp;=\u0026thinsp;1.54\u0026ndash;1.76, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;2.05 x 10⁻⁴⁹), and allergic rhinitis (OR\u003csub\u003ecross\u003c/sub\u003e = 1.95, 95% CI\u0026thinsp;=\u0026thinsp;1.85\u0026ndash;2.05, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;3.52 x 10⁻\u0026sup1;⁴⁴). However, there were a few respiratory diagnoses that showed lower odds of fibroids including pleurisy, pulmonary collapse, and respiratory failure (ORs\u003csub\u003ecross\u003c/sub\u003e = 0.35\u0026ndash;0.50, 95% CIs\u0026thinsp;=\u0026thinsp;0.32\u0026ndash;0.55 \u003cem\u003ep\u003c/em\u003e-values\u0026thinsp;\u0026lt;\u0026thinsp;5.00 x 10⁻\u0026sup3;⁶).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eRacially Stratified Meta-Analyses\u003c/h2\u003e \u003cp\u003eAll 169 phecodes that were meta-analyzed in the Black population were significantly associated with uterine fibroids after adjustment for multiple testing (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB). Of the 377 phecodes which were meta-analyzed in the White populations, 369 (~\u0026thinsp;98%) were significantly associated with fibroids and only eight phecodes did not reach significance after adjusting for multiple testing (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eC). Known risk factors, including overweight/obesity, other hypertrophic and atrophic conditions of skin, and pelvic inflammatory disease, were significantly associated with fibroids in both groups (Table\u0026nbsp;4). Symptoms often associated with fibroids, such as dysuria, pain and other symptoms associated with female genital organs, ovarian cysts, and malaise and fatigue, were also associated with fibroid diagnosis in both groups. In general, the association between fibroid status and several known and novel factors was greater in Black females relative to White females (e.g., vitamin D deficiency OR\u003csub\u003eblack =\u003c/sub\u003e 2.00, 95% CI\u0026thinsp;=\u0026thinsp;1.71\u0026ndash;2.33, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;7.74 x 10\u003csup\u003e⁻\u0026sup1;⁹\u003c/sup\u003e, OR\u003csub\u003ewhite\u003c/sub\u003e = 1.36, 95% CI\u0026thinsp;=\u0026thinsp;1.28\u0026ndash;1.44, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.57 x 10⁻\u0026sup2;\u0026sup3;; endometriosis OR\u003csub\u003eblack\u003c/sub\u003e = 9.51, 95% CI\u0026thinsp;=\u0026thinsp;6.91\u0026ndash;13.08, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;1.30 x 10⁻⁴\u0026sup3;, OR\u003csub\u003ewhite\u003c/sub\u003e = 7.66, 95% CI\u0026thinsp;=\u0026thinsp;6.75\u0026ndash;8.70, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.84 x 10⁻\u0026sup2;\u0026sup1;⁷), though there were a few instances where the opposite was true (e.g., benign neoplasm of ovary OR\u003csub\u003eblack\u003c/sub\u003e = 20.23, 95% CI\u0026thinsp;=\u0026thinsp;13.04\u0026ndash;31.38, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;4.86 x 10⁻⁴\u0026sup1;, OR\u003csub\u003ewhite\u003c/sub\u003e = 27.17, 95% CI\u0026thinsp;=\u0026thinsp;21.24\u0026ndash;34.76, \u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;=\u0026thinsp;5.10 x 10⁻\u0026sup1;⁵\u0026sup2;). Several novel associations were observed in both Black and White populations, including genitourinary diagnoses such as genital prolapse and polyps of female genital organs (Table\u0026nbsp;4, Supplemental Table\u0026nbsp;1\u0026ndash;2).\u003c/p\u003e \u003cp\u003eThere was an overall enrichment for positive relationships in both meta-analyses, demonstrating a marked increase in comorbidities in individuals with uterine fibroids compared to those without fibroids (Table\u0026nbsp;5). Within Black and White females and across ancestries, genitourinary diagnoses represent the highest proportion of significant replicated associations (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB, \u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC). Diagnoses in the circulatory, endocrine/metabolic, respiratory, neoplasm, and musculoskeletal groups followed, but exact rank varied by race. All diagnoses within the and musculoskeletal group were positively associated with fibroids, suggesting that fibroids and at least one musculoskeletal diagnosis or symptom co-occur. Both within and across races, diagnoses in the genitourinary group tended to be positively associated with fibroids (Tables\u0026nbsp;4\u0026ndash;5), while circulatory diagnoses were associated with negatively correlated and tied to decreased odds of fibroids (Tables\u0026nbsp;4\u0026ndash;5). Diagnoses in the dermatologic and sense organ groups were only positively associated with fibroids in White females alone (Table\u0026nbsp;5).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eUsing a validated, multi-stage PheWAS, we found significant associations between fibroid status and multiple disease categories, with the strongest risk factors being among genitourinary, musculoskeletal, and neoplasms. Importantly, known fibroid risk factors, such as inflammatory diseases of female pelvic organs, disorders of menstruation and other abnormal bleeding from the female genital track, dysmenorrhea, hyperlipidemia, and vitamin D deficiency, were the most strongly associated diagnoses, highlighting the validity of our method. Outside these known risk factors, we also identified several novel diagnoses associated with uterine fibroids, including neoplasms and diagnoses linked to autoimmunity. In general, females with uterine fibroids had a significantly higher number of co-morbid diagnoses relative to control individuals. Across disease groups, diagnoses tended to be positively associated with fibroids within and across race groups, suggesting that fibroids are associated with increased comorbidities in many disease groups.\u003c/p\u003e \u003cp\u003eGenitourinary diagnoses, such as symptoms related to menstruation (frequent, irregular, excessive), dysmenorrhea, pain in female genital organs, disorders of the urinary system, and early menopause, were the strongest associations. These diagnoses are the most typical symptoms frequently reported by individuals with symptomatic fibroids, further highlighting the validity of our phenotyping algorithm and PheWAS approach \u003csup\u003e\u003cspan additionalcitationids=\"CR25 CR26\" citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Our results also confirm previously identified relationships between other genitourinary diagnoses and uterine fibroids. For example, there was strong relationship between leiomyoma and endometriosis. Previous studies that have identified a positive relationship between endometriosis and fibroids, as well as evidence of a common genetic basis between the two conditions \u003csup\u003e\u003cspan additionalcitationids=\"CR29 CR30\" citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eKnown risk factors and related conditions, outside of genitourinary diagnoses, were also observed. For example, diagnoses related to BMI, an established risk factor for fibroids, were more common in individuals with fibroids regardless of race. These diagnoses, including obesity and disorders of lipid metabolism, are also established risk factors for leiomyoma \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e,\u003cspan additionalcitationids=\"CR33\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. Our models were adjusted for BMI, suggesting other pathways or nonlinear relationships with BMI between fibroids and these traits.\u003c/p\u003e \u003cp\u003eVitamin D deficiency was significantly associated with fibroids. Case-control studies have found lower Vitamin D levels in females with uterine fibroids \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan additionalcitationids=\"CR36\" citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e. Lower levels of Vitamin D have also been observed in Black females \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Our study found that Black individuals with Vitamin D deficiency had higher odds of fibroid diagnosis relative to White individuals. \u003cem\u003eIn vitro\u003c/em\u003e studies have identified a role of Vitamin D in reducing the expression of key genes related to extracellular matrix production in fibroid cells \u003csup\u003e\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. Diagnosis with atrophic skin conditions also increased odds of uterine fibroid diagnosis \u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur study identified several novel associations. Briefly, diagnoses such as inflammatory pelvic disease, non-inflammatory pelvic disease, and benign mammary dysplasia, which were not previously well-documented as associated with fibroids, were associated with increased odds of fibroids. As with leiomyomas, many of these genitourinary diagnoses are related to estrogen or hormone dysregulation (endometrial hyperplasia, endometriosis, pelvic inflammatory disease, cystic mastopathy)\u003csup\u003e\u003cspan additionalcitationids=\"CR43 CR44 CR45 CR46 CR47 CR48\" citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e. These findings suggest a plausible etiologic mechanism shared across genitourinary disease: hormone dysregulation \u003csup\u003e\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e50\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eFibroids are generally considered as benign neoplasms \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e51\u003c/span\u003e,\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e52\u003c/span\u003e\u003c/sup\u003e. However, our findings suggest common underlying biology of fibroids and both benign and malignant neoplasms. The second largest association, after benign neoplasms of the uterus (the parent code for fibroids), was malignant neoplasm of the uterus. Cervical cancer, cervical intraepithelial dysplasia, abnormal Papanicolaou smear of cervix uterine, cervical and genital polyps, as well as benign neoplasms of the ovary and breast were also positively associated with fibroids. If fibroids or polyps develop prior to genitourinary and reproductive malignancies, these conditions could risk factors and may be useful in screening tests.\u003c/p\u003e \u003cp\u003eDiagnoses in the circulatory system category, such as ischemic heart disease, peripheral vascular disease, and congestive heart failure, were consistently associated with reduced odds of uterine fibroid diagnosis. Hypotension not otherwise specified was also negatively associated with fibroids, consistent with reports of high blood pressure and hypertension increasing risk of fibroids \u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e53\u003c/span\u003e,\u003cspan citationid=\"CR55\" class=\"CitationRef\"\u003e54\u003c/span\u003e\u003c/sup\u003e. These results suggest an underlying mechanism linking biology of cardiovascular function and uterine fibroids. Estrogen, which has been associated with fibroid development, has known protective effects for cardiovascular disease \u003csup\u003e\u003cspan citationid=\"CR56\" class=\"CitationRef\"\u003e55\u003c/span\u003e\u003c/sup\u003e. Interestingly, obesity and metabolic disorders are typically associated with increased risk of vascular disease \u003csup\u003e\u003cspan additionalcitationids=\"CR57\" citationid=\"CR57\" class=\"CitationRef\"\u003e56\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR59\" class=\"CitationRef\"\u003e58\u003c/span\u003e\u003c/sup\u003e. The links between leiomyoma, obesity, metabolic disease, and cardiovascular outcomes suggests more complex relationships between the physiology of these diagnoses that requires further research.\u003c/p\u003e \u003cp\u003eWe did not observe a consistent pattern of increased or decreased odds of fibroids within other disease groups. However, when comparing associations across remaining disease groups, we observed increased odds with immune/inflammation pathways. For example, respiratory diagnoses such as acute bronchiolitis, chronic and acute sinusitis, and upper respiratory infections were associated with increased odds of fibroids. Similarly, other disease groups like symptoms (cervical radiculitis, thoracic neuritis/radiculitis, cervicalgia\u003csup\u003e\u003cspan citationid=\"CR60\" class=\"CitationRef\"\u003e59\u003c/span\u003e\u003c/sup\u003e), digestive (irritable bowel syndrome \u003csup\u003e\u003cspan citationid=\"CR61\" class=\"CitationRef\"\u003e60\u003c/span\u003e\u003c/sup\u003e), musculoskeletal (synovitis/tenosynovitis, pain and stiffness in joint \u003csup\u003e\u003cspan citationid=\"CR62\" class=\"CitationRef\"\u003e61\u003c/span\u003e\u003c/sup\u003e) and dermatological (dyschromia and vitiligo \u003csup\u003e\u003cspan citationid=\"CR63\" class=\"CitationRef\"\u003e62\u003c/span\u003e\u003c/sup\u003e, alopecia \u003csup\u003e\u003cspan citationid=\"CR64\" class=\"CitationRef\"\u003e63\u003c/span\u003e\u003c/sup\u003e) diagnoses, which are linked with immune and/or inflammation, are also associated with increased odds of fibroids in our study. Inflammatory processes and dysregulation have previously been suggested to be involved in the development of uterine fibroids \u003csup\u003e\u003cspan citationid=\"CR65\" class=\"CitationRef\"\u003e64\u003c/span\u003e\u003c/sup\u003e, endometrial disorders \u003csup\u003e\u003cspan citationid=\"CR66\" class=\"CitationRef\"\u003e65\u003c/span\u003e\u003c/sup\u003e, and cardiovascular disease via metabolic syndrome \u003csup\u003e\u003cspan citationid=\"CR67\" class=\"CitationRef\"\u003e66\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn general, Black and White females showed similar patterns in associations. The race-specific associations tended to have related diagnoses that were significant in the cross-ancestry meta-analysis or in White females. For example, fluid overload is significant only in Black females, however, the related diagnosis of \u0026ldquo;disorders of fluid, electrolyte, and acid base balance\u0026rdquo; is significant in both races and meta-analysis. The disparity in associations between Black and White females suggests both genetic and non-genetic differences. However, it is also possible that such a large disparity is a result of lack of statistical power due to the smaller sample size of Black cases relative to White cases. Further research is needed to replicate these differences and uncover any racial disparities in diagnoses.\u003c/p\u003e \u003cp\u003ePheWAS provides a unique way to test for comorbidities and patterns of disease in a systematic fashion. This method is dependent on EHR diagnostic and billing codes, the entry of which do not always correspond to true disease presence. Reliance on these codes could lead to bias due to misclassification. However, validation in two different EHR databases, where clinical practice and coding is likely to vary, lessens the probability that significant results are due to bias or chance. Furthermore, fibroid cases and controls were identified using our previously published algorithm, which was previously shown to have high performance. A stringent significance threshold by Bonferroni correction was also adopted to further reduced the chance of false associations. The successful identification of the well-known risk factors indicates the validity of these methods to detect real relationships. However, the associations identified in this study do not implicate causality. A well-controlled longitudinal study may provide more insight in the causal direction between fibroids and other diseases.\u003c/p\u003e \u003cp\u003eWe validated previously reported risk factors and identified novel diagnoses that have not been previously linked to uterine fibroids. In general, females with uterine fibroids bear a larger burden of comorbid traits across most disease-diagnosis groups. We detected novel significant associations of fibroids with malignant neoplasms in the uterus and cervix, as well decreased negative associations with cardiovascular diagnoses and positive associations with inflammation related diseases. This study provides the most detailed systematic research into fibroids and comorbidities to-date by leveraging large scale EHR databases and PheWAS methodology and demonstrates a novel approach to identifying previously uncharacterized comorbidities of uterine fibroids.\u003c/p\u003e"},{"header":"Materials and Methods","content":"\u003cp\u003e \u003cb\u003eStudy Populations.\u003c/b\u003e \u003c/p\u003e \u003cp\u003eWe utilized Vanderbilt University Medical Center\u0026rsquo;s (VUMC) Synthetic Derivative (SD) for our discovery analyses. The SD is a de-identified mirror of the VUMC EHRs containing longitudinal data, including demographic and clinical information, for over 3\u0026nbsp;million subjects who have received care in the VUMC healthcare system \u003csup\u003e\u003cspan citationid=\"CR68\" class=\"CitationRef\"\u003e67\u003c/span\u003e\u003c/sup\u003e. Non-Hispanic Black and White females 18 years or older were eligible for inclusion, with race and ethnicity defined via self-reported or by providers. Cases and controls were identified using our previously published algorithm, which has been shown to have positive and negative predictive values of 96% and 98% respectively \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Briefly, cases had at least one International Classification of Diseases, 9th Revision (ICD-9) or current procedure terminology (CPT) code for pelvic imaging and had at least one ICD-9 or CPT code indicating a fibroid diagnosis. Controls had at least two procedural codes for pelvic imaging without a fibroid diagnosis at time of last pelvic exam, as well as no history of hysterectomy, myomectomy, or uterine artery embolization.\u003c/p\u003e \u003cp\u003eThe Geisinger Health System (GHS) Database was used as a validation cohort, with cases and controls identified by the algorithm described above. GHS is a fully integrated health system serving three million residents of north-central and northeastern Pennsylvania. The database comes from GHS\u0026rsquo;s physician group practices which includes a network of 1,000 physicians across 75 sites, inclusive of 41 community care clinics.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStatistical Analyses.\u003c/b\u003e \u003c/p\u003e \u003cp\u003ePheWAS, adjusted for age and BMI, were performed with uterine fibroids as the outcome and each diagnosis, condition, or clinical characteristic (phecode) as an exposure. Analyses were performed using the PheWAS package (v 0.99.5-3) in R \u003csup\u003e\u003cspan citationid=\"CR69\" class=\"CitationRef\"\u003e68\u003c/span\u003e\u003c/sup\u003e. Discovery PheWAS was first performed in the SD before significant results were validated in GHS cohort (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). A Bonferroni correction based on the number of tests in discovery population was used to determine significance (\u003cem\u003ep\u003c/em\u003e-value\u0026thinsp;\u0026le;\u0026thinsp;2.98 x 10⁻⁵ for Black individuals, 2.87 x 10⁻⁵ for White individuals, 2.99 x 10⁻⁵ for cross-ancestry). Phecodes from significant associations in the discovery population were then carried forward through testing in the validation population. Inverse-variance weighted fixed-effects meta-analyses was performed, using METAL software, for associations that were significant in the discovery population and had the same direction of effect in both the discovery and validation analyses \u003csup\u003e\u003cspan citationid=\"CR70\" class=\"CitationRef\"\u003e69\u003c/span\u003e\u003c/sup\u003e. Race-stratified and cross-ancestry meta-analyses were performed across the cohorts. Bonferroni p-values for the meta-analyses were based on the number of significant phecodes in the discovery populations that were available and in the same direction in the validation populations (Black: 2.55 x 10⁻⁴; White: 1.33 x 10⁻⁴, Cross-ancestry 1.28 x 10⁻⁴). Secondary analyses, adjusting for only age, were also performed (Supplemental Table\u0026nbsp;4).\u003c/p\u003e \u003cp\u003eUsing previously described methods, phecodes were classified into 16 disease groups based largely off of organ systems and/or biologic processes \u003csup\u003e\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e. A binomial test was used to test for directional relationships of significant associations across all tests, as well as to test for directional relationships within disease categories within stratified meta-analyses and cross-ancestry meta-analysis. A Bonferroni correction was used to determine significance in tests within disease categories.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eCompeting Interests\u003c/h2\u003e \u003cp\u003eThe authors report no conflict of interest.\u003c/p\u003e \u003c/p\u003e\u003ch2\u003eAuthor Contributions\u003c/h2\u003e \u003cp\u003eE.A.J. and B.S.M. conceptualized and designed the study, performed analyses, interpreted the results, and prepared the initial article, and reviewed and revised the manuscript. J.N.H. and J.A.P. contributed to the design of the study, analyses, interpretation, and preparation of the manuscript. Y.Z. performed analyses and revised the manuscript. S.H.J., S.A.P., and M.L.M., reviewed and substantially revised the manuscript. E.S.T. aided in data acquisition and revised the manuscript. T.L.E. and D.R.V.E. conceptualized and designed the study, coordinated, and supervised data acquisition and storage, made substantial contributions to the interpretation of results, and critically revised the manuscript. All authors approved the final article as submitted and agree to be accountable for all aspects of the work.\u003c/p\u003e\u003ch2\u003eAcknowledgements\u003c/h2\u003e \u003cp\u003eD.R.V.E. was supported by National Institute of Health grants R01HD074711, R01HD093671, and R03HD078567. T.E. was supported by The Vanderbilt Clinical and Translational Research Scholar Award 5KL2-RR024977 from the National Center for Advancing Translational Sciences. B.S.M was supported by National Cancer Institute grant T32 CA160056. E.A.J. and J.N.H. were supported by the NIH Building Interdisciplinary Research Career's in Women's Health career development program (K12HD043483 PIs: K.E. Hartmann, A.S. Major, and D.R.V.E.).\u003c/p\u003e\u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eData Availability Statement\u003c/h2\u003e \u003cp\u003eData for this manuscript cannot be made readily available but is readily available through IRB approval to either Vanderbilt University Medical Center or Geisinger Health System employees.\u003c/p\u003e \u003c/div\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eCardozo, E. R.\u003cem\u003e et al.\u003c/em\u003e The estimated annual cost of uterine leiomyomata in the United States. \u003cem\u003eAmerican Journal of Obstetrics and Gynecology\u003c/em\u003e \u003cstrong\u003e206\u003c/strong\u003e, 211.e211-211.e219, doi:10.1016/j.ajog.2011.12.002 (2012).\u003c/li\u003e\n\u003cli\u003eBaird, D. D., Dunson, D. B., Hill, M. C., Cousins, D. \u0026amp; Schectman, J. M. 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METAL: fast and efficient meta-analysis of genomewide association scans. \u003cem\u003eBioinformatics\u003c/em\u003e \u003cstrong\u003e26\u003c/strong\u003e, 2190-2191, doi:10.1093/bioinformatics/btq340 (2010).\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1-5 are available in the Supplementary Files section.\u003c/p\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":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"uterine fibroids, leiomyoma, disease burden, electronic health records, phenome-wide association study ","lastPublishedDoi":"10.21203/rs.3.rs-3998063/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3998063/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThe burden of comorbidities in those with uterine fibroids compared to those without fibroids is understudied. We performed a phenome-wide association study to systematically assess the association between fibroids and other conditions. Vanderbilt University Medical Center\u0026rsquo;s Synthetic Derivative and Geisinger Health System Database, two electronic health record databases, were used for discovery and validation. Non-Hispanic Black and White females were included. Fibroid cases were identified through a previously validated algorithm. Race-stratified and cross-ancestry analyses, adjusting for age and body mass index, were performed before significant, validated results were meta-analyzed. There were 52,200 and 26,918 (9,022 and 10,232 fibroid cases) females included in discovery and validation analyses. In cross-ancestry meta-analysis, 389 conditions were associated with fibroid risk with evidence of enrichment of circulatory, dermatologic, genitourinary, musculoskeletal, and sense organ conditions. The strongest associations within and across racial groups included conditions previously associated with fibroids. Numerous novel diagnoses, including cancers in female genital organs, were tied to fibroid status. Overall, individuals with fibroids had a marked increase in comorbidities compared to those without fibroids. This novel approach to evaluate the health context of fibroids highlights the potential to understand fibroid etiology through studying common biology of comorbid diagnoses and through disease networks.\u003c/p\u003e","manuscriptTitle":"A Phenome-Wide Association Study of Uterine Fibroids Reveals a Marked Burden of Comorbidities","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-14 19:43:05","doi":"10.21203/rs.3.rs-3998063/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"communications-medicine","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"commsmed","sideBox":"Learn more about [Communications Medicine](http://www.nature.com/commsmed)","snPcode":"43856","submissionUrl":"https://mts-commsmed.nature.com/cgi-bin/main.plex","title":"Communications Medicine","twitterHandle":"@commsmedicine","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Communications Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"201399e0-f99d-472b-98c8-c95f9cdf1115","owner":[],"postedDate":"March 14th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":29155316,"name":"Health sciences/Diseases/Reproductive disorders/Urogenital reproductive disorders"},{"id":29155317,"name":"Health sciences/Signs and symptoms/Comorbidities"}],"tags":[],"updatedAt":"2025-05-16T07:10:51+00:00","versionOfRecord":{"articleIdentity":"rs-3998063","link":"https://doi.org/10.1038/s43856-025-00884-w","journal":{"identity":"communications-medicine","isVorOnly":false,"title":"Communications Medicine"},"publishedOn":"2025-05-15 04:00:00","publishedOnDateReadable":"May 15th, 2025"},"versionCreatedAt":"2024-03-14 19:43:05","video":"","vorDoi":"10.1038/s43856-025-00884-w","vorDoiUrl":"https://doi.org/10.1038/s43856-025-00884-w","workflowStages":[]},"version":"v1","identity":"rs-3998063","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3998063","identity":"rs-3998063","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}