The burden of endometriosis on quality of life in Danish blood donors

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Kogelman, Dorte Rytter, Lone Hummelshoj, Karina Ejgaard Hansen, and 22 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6620337/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 14 Oct, 2025 Read the published version in BMC Medicine → Version 1 posted 9 You are reading this latest preprint version Abstract Background : Endometriosis is a complex condition with a wide range of comorbidities. It is widely underdiagnosed, with a diagnostic delay of 4 to 10 years, potentially leading to worsened disease progression and a higher burden of comorbidities affecting quality of life. Understanding the link between endometriosis and its comorbidities is essential for improving early detection of the disease. Methods : We analysed data from 953 women with a clinical diagnosis of endometriosis and 23,652 age-matched female controls enrolled in the Danish Blood Donor Study. Participants completed one to four questionnaires covering a wide range of potential comorbidities; genetic data were available for a subset of participants. First, we compared the potential comorbidities between women with endometriosis and controls. Next, we investigated whether a polygenic score (PGS) for endometriosis was associated with those comorbidities. Lastly, we investigated whether women with a high genetic burden of endometriosis (highest PGS decile) experienced similar comorbidities to those diagnosed with endometriosis. Results : Women with endometriosis experienced challenges in conception, gastrointestinal symptoms, disturbed sleep patterns, and slightly lower mental health scores, compared to age-matched controls. The endometriosis PGS showed to be a predictor for endometriosis (OR per unit PGS = 1.43, 95% CI = 1.32 – 1.55). Gastrointestinal symptoms were also associated with the endometriosis PGS, indicating shared genetic pathways. Women without a diagnosis of endometriosis but with a high genetic burden of endometriosis did not suffer from the same wide range of comorbidities as women diagnosed with endometriosis. Conclusions : Our findings highlight the complex genetic and clinical relationships between endometriosis and its comorbidities emphasizing the need for future research investigating potential endometriosis subtypes. endometriosis comorbidities polygenic score genetic burden Figures Figure 1 Figure 2 Background Endometriosis is a complex condition that imposes a substantial economic burden 1 , 2 . It is estimated to affect approximately 10% of reproductive-age women worldwide, although prevalence varies depending on diagnostic criteria and population characteristics 3 , 4 . Endometriosis extends far beyond its primary manifestation of endometrial-like tissue outside the uterus to a large range of comorbidities, such as infertility, persistent abdominal pain, gastrointestinal complications, migraine, and challenges related to mental health 5 – 10 . Endometriosis is widely underdiagnosed 11 – 13 , with a diagnostic delay of 4 to 10 years 14 – 17 which leads to delayed treatment and prolonged patient suffering 10 , 18 . This diagnostic delay not only exacerbates disease progression but may also contribute to an increased burden of comorbid conditions. Understanding the relationship between endometriosis and its comorbidities is crucial for enabling early detection, improving patient outcomes, and build comprehensive management strategies. Although the exact aetiology of endometriosis is still not fully understood, substantial evidence suggests a significant genetic component in the risk of developing the condition, with an estimated heritability of around 50% 19,20 . Genome-wide association studies (GWAS) have identified 42 common genetic loci associated with the risk of endometriosis 21 with moderate to small effect sizes. Due to the moderate to small effect sizes, common in complex diseases 22 , there is considerable interest in consolidating the impacts of multiple genetic risk variants into a combined score. A commonly employed scoring method involves calculating the sum of risk alleles, with each single nucleotide variant weighted by its GWAS effect size – known as a polygenic score (PGS) 23 , 24 . Because the PGS has a theoretical relationship with the genetic liability model of polygenic diseases it has led to widespread use of PGS in biomedical research 24 . We hypothesize that the observed comorbidities are intricately linked to the genetic burden of endometriosis. In this study, we investigate 37 comorbidities of endometriosis in up to 24,605 individuals participating in the Danish Blood Donor Study (DBDS) 25 . By constructing a genome-wide PGS for endometriosis, we assess to what degree the genetic burden of endometriosis was associated with comorbidities of endometriosis. This approach enhances our understanding of the impact of endometriosis on quality of life and the potential association of endometriosis with genetic factors. Methods Study population . From March 2010 to December 2022 voluntary blood donors were recruited as part of the Danish Blood Donor Study (DBDS), an ongoing prospective population-based research cohort 25 . Eligible participants were aged 18–67 years and weighing > 50 kg. Blood donors are subject to strict eligibility criteria as defined by the Transfusion Medicine Standards ( https://dski.dk/gaeldende-version/ ). Participating blood donors completed between one to four different questionnaires during the recruitment period. The first version was a paper-based questionnaire, whilst the following three were digital questionnaires. Questionnaires covered questions on self-experienced physical and mental health (including the Short Form Health Survey 12 [SF-12] 26 ), smoking habits, sleep patterns, allergies, attention-deficit/hyperactivity disorder (ADHD), migraine, depression, pregnancy, gastrointestinal symptoms, and many other health-related conditions. Diagnosis of endometriosis. The Danish National Patient Registry (DNPR) contains data on all in- and outpatients discharged from Danish hospitals since 1977 and, since 2002, it also includes records from Danish private hospitals. An endometriosis diagnosis was defined based on the presence of any of the codes: ICD-8 codes 62.530 and 62.532–62.539 (< 1994) and ICD-10 codes N80.1-N80.9 (≥ 1994) in the DNPR, regardless of surgical or histologic verification. Adenomyosis diagnoses (ICD8: 62531, ICD10: N80.0) were not included. The date of diagnosis was based on the hospital admission date for the first endometriosis diagnosis. For each questionnaire, a participant was counted as an endometriosis-case when, at the time of filling out the questionnaire, the individual had a diagnosis of endometriosis in DNPR. Diagnoses were subdivided into ‘deep endometriosis’ (ICD8: 62535, 62536; ICD10: N80.4, N80.5), ‘ovarian endometriosis ‘(ICD8: 62530; ICD10: N80.1), ‘peritoneal endometriosis’ (ICD8: 62532, 62533; ICD10: N80.2, N80.3), and ‘other endometriosis’ (ICD8: 62537, 62538; ICD10: N80.6, N80.8, N80.9). Severity of endometriosis was divided into severe (i.e. stage III/IV endometriosis including ‘deep’ and/or ‘ovarian’- endometriosis) and moderate (i.e., stage I/II endometriosis including ‘peritoneal’ and/or ‘other’- endometriosis according to the r-ASRM score) 27 . Age-matching. Female blood donors with an endometriosis diagnosis were significantly older than females without endometriosis (45.7 versus 44.6 years, p = 2.28×10 − 3 ). Therefore, for each questionnaire, an age-matched female study population was selected from the DBDS cohort, with a case:control ratio of ~ 1:25 (Table 1 ). At the time of filling in the respective questionnaires, the ‘case’ had to have an endometriosis diagnosis; ‘controls’ were not diagnosed with endometriosis at any point throughout the complete study period (8 March 1977–9 November 2022) and all had genetic data available. Genetic data. The majority of the DBDS participants have genetic information available ( n = 100,146), which established the DBDS Genomic Cohort 28 . A total of 649 women with endometriosis and all 23,652 age-matched female controls had genetic information available (Table 1 ). At inclusion, a blood sample for DNA analyses was collected and saved in the biobank. DNA genotyping of the DBDS samples was obtained at deCODE Genetics using the Global Screening Array by Illumina. The raw genotype data was processed at deCODE genetics simultaneously for genotype calling, quality control and genotype imputation using an in-house reference panel consisting of UK 1KG phase 3, HapMap reference and an in-house dataset of > 6,000 Danish whole genome sequences 29 . Genetic principal components (PCs) for the study cohort were calculated on a reduced dataset of 30,966 genetic variants by linkage disequilibrium (LD) pruning using PLINK 30 . PCs were calculated using flashPCA 31 and the resulting PCs were included in subsequent analyses to account for population stratification. Any related individuals were removed from the data (up to second degree relatives) to avoid inflated predictions in subsequent analysis. Table 1 Overview of questionnaires and a breakdown of the number of individuals ( n ) with questionnaire (Q) and genetic (G) data available Questionnaire Time n Endometriosis (Q|G) Control DBDS1 03/2010–01/2015 526|471 11,572 DBDS2 05/2015–06/2018 350|266 10,016 DBDS3 06/2018–03/2020 308|190 7,051 DBDS4 11/2020–11/2022 301|153 6,575 Total (unique) 03/2010–11/2022 953|649 23,652 * n : count, Q: questionnaire data available, G: genetic information available. Selected controls all had both questionnaire and genetic data available. Assessing comorbidities. All questions used in this study are presented in Supplementary Table 1; participants only received the Danish question. Questionnaire data was pre-processed at question level by excluding individuals who answered, “Do not know”. Several questions were part of a scoring system, where multiple questions were combined into a single scale. Insomnia was defined as experiencing at least one of three symptoms ≥ 3 times per week: (1) difficulty falling asleep within 30 minutes, (2) waking up too early and unable to fall back asleep, or (3) woken up during the night or early morning. Daytime fatigue was defined as experiencing at least one of three symptoms ≥ 3 times per week: (1) extreme tiredness during the day, (2) an irresistible urge to sleep at work/school, and (3) an irresistible urge to sleep during spare time. Restlessness in legs during sleep was identified when participants reported experiencing restless legs ≥ 3 times per week. Physical and mental health status was measured using the 12-item Short Form Health Survey (SF-12), which yields two composite scores: the physical component summary score (PCS) and the mental component summary score (MCS) 32 . Scores were calculated using weighted item endorsements, yielding values between 0 and 100, with higher scores reflecting better quality of life 33 . Perceived stress was measured using the 10-item Cohen’s Perceived Stress Scale (PSS) 34 . The questions were answered on a 5-point Likert scale, asking the respondents to indicate how often they experience a specific stress symptom ranging from “0 = never” to “4 = very often”, resulting in a score ranging from 0 to 40. Depression was measured using the Major Depression Inventory (MDI): a validated self-report questionnaire of 10 items ranging from 0 to 5 35,36 . The MDI score was calculated as the sum of all 10 items, including only the item with the highest score out of item 8a and 8b, and similarly the one with the highest score out of item 10a and 10b. Depression was analysed both on a continuous scale (MDI score) and classification of depression using a cut-off of > 20. As participants might have donated blood more than once during the 12-year period they may have participated in multiple questionnaires. When a question was asked more than once (e.g., smoking behaviour and body mass index), the answer in the most recent questionnaire was used in this study. For women with endometriosis, the most recent questionnaire after having received an endometriosis diagnosis was used. Polygenic score for endometriosis. The endometriosis PGS, representing the genetic burden of endometriosis, was constructed utilising GWAS summary data from the most recent endometriosis meta-GWAS 21 , where cases and controls from the DBDS cohort and the 23andMe cohort were excluded to avoid sample overlap. The endometriosis PGS was calculated using LDpred2 software 37 using the auto option with default settings. The endometriosis PGS was standardized to a mean of zero and standard deviation of 1, and when used to measure the prediction accuracy for the comorbidities, the endometriosis PGS was rescaled to a mean of zero and one unit standard deviation corresponding to a twofold genetic increased risk for endometriosis in the target population; this was done by subtracting the mean PGS from each individuals’ PGS and then multiplying by log(OR)/log(2), where the odds ratio (OR) was obtained from the model predicting endometriosis (see below). To investigate whether participants with a high genetic burden for endometriosis exhibit similar comorbidities as women diagnosed with endometriosis, we selected a subset of controls whose PGS values were in the top decile of the PGS distribution. Statistical analyses. Differences in comorbidities between those diagnosed with endometriosis and female participants without were compared using Student's t-tests (continuous traits), \(\:{\chi\:}^{2}\) -squared test (binomial traits), or Wilcoxon signed-rank test (ordinal traits). All analyses were corrected for age and blood donation region (i.e. the region of Denmark where the participant donated blood), as we found significant differences in endometriosis diagnosis between the different regions of Denmark in concordance with a previous study (Illum et al., 2022). Resulting p -values were corrected for multiple testing, based on the number of tests performed (n = 37) using the False Discovery Rate (FDR) 38 . Statistical differences between endometriosis cases and controls were determined significant when P FDR < 0.05. Further, we investigated whether there were differences in comorbidities between women with stage I/II endometriosis compared to women with stage III/IV endometriosis using the same model as described above. Similar, resulting p-values were corrected for multiple testing using the FDR, and determined significant when P FDR < 0.05. Only comorbidities that were significantly associated with endometriosis were subsequently associated with the endometriosis PGS using a logistic regression including region and the first five genetic PCs as covariates. The discriminative ability of the PGS was determined using the area under the receiver operating curve (AUC). Comorbidities that displayed an association with endometriosis PGS of P FDR < 0.05 were considered significant. Significant predictions were presented as odds ratios with 95% confidence intervals, using the rescaled PGS, i.e., one standard deviation of the PGS corresponds to a twofold genetic increased risk for endometriosis. All statistical analyses were performed in R (v4.0.0). Results From 24,605 females selected from the DBDS cohort for this study, 953 females were diagnosed with endometriosis at the time of filling in (one of) the questionnaires. A summary of our findings is presented in Figure 1. The majority of women with endometriosis were diagnosed with one morphological location of endometriosis ( n =521), while 225 were diagnosed with endometriosis in two locations, and 178 with three or more locations. The remaining 29 were not diagnosed with a specific endometriosis location. Of the 953, 534 (56%) were categorized as moderate endometriosis (stage I/II) and 419 (44%) as severe endometriosis (stage III/IV). General characteristics of women with endometriosis On average, endometriosis was diagnosed at the age of 33.0 (SD = 8.3) years. Before age-matching, we found a prevalence proportion for endometriosis of 1.28%. Even though the prevalence proportions differed by region of Denmark ( p <0.001), we did not see a significant difference in age at diagnosis between the regions ( p = 0.05). Women diagnosed with endometriosis had similar body mass index (BMI), standing height, and waist circumference as the female controls (Table 2), and there was no difference in frequency of smoking (or smoking in the childhood home) observed between women with endometriosis and their aged-matched controls (Table 2). Table 2. Descriptive statistics of the cohort Characteristics n (E/C) Endometriosis Controls P FDR BMI, mean (SD) 941/23,487 25.9 (4.8) 25.6 (4.7) 1.00 Height, mean (SD) 951/23,606 169.1 (6.2) 168.8 (6.0) 1.00 Waist circumference, mean (SD) 482/10,526 87.3 (11.1) 86.0 (11.4) 1.00 Smoking, % 950/18,517 15.7 15.4 1.00 Smoking in childhood home, % 524/11,357 74.6 65.5 1.00 Genetic risk of endometriosis predicts endometriosis and its severity The DBDS genomic cohort included 649 endometriosis cases and 23,652 age-matched controls. The average standardized endometriosis PGS was significantly higher in women with endometriosis than in controls (Figure 2A), with an OR for endometriosis of 1.43 (95% CI = 1.32 – 1.55) and AUC of 0.66 ( p <0.001). The age of endometriosis diagnosis was not significantly associated with the endometriosis PGS ( p = 0.99). The endometriosis PGS was higher in all endometriosis subtypes, except for ‘ other’ ( p = 0.55), compared to the controls (Table 3) and was higher among women with stage III/IV endometriosis than women with stage I/II endometriosis ( p = 2.11×10 -3 ). The endometriosis PGS was also higher in women with endometriosis at multiple locations (OR = 1.30, 95% CI = 1.14 - 1.49, p < 0.001) Furthermore, individuals in the top 10 percent of PGS had more than double the risk for endometriosis compared to individuals with a median PGS (Figure 2B-C). Table 3. Prediction of endometriosis at different locations using the polygenic score (PGS) of endometrioses. n * PGS (mean [SD]) AUC P FDR Endometriosis (any) 649 0.35 (1.01) 0.66 <0.001 Deep 78 0.51 (1.07) 0.75 <0.001 Ovarian 253 0.49 (0.99) 0.68 <0.001 Peritoneal 215 0.47 (0.98) 0.69 <0.001 Other 396 0.36 (1.03) 0.67 <0.001 Abbreviations: n = number of cases; PGS = standardized polygenic score; AUC = area under the receiver operating characteristic curve; P FDR = false discovery rate. * Tested against all (n=23,652) controls Reproductive health in women with endometriosis The reproductive health of women with endometriosis was different to the aged-matched female controls (Table 4). Women with endometriosis reported no earlier age at menarche compared to controls, neither did we find a difference in menstrual cycle length. Furthermore, among women who entered menopause at the time of filling out the questionnaire, we found an earlier age of induced onset of menopause (three years earlier), but not in natural menopause. The severity of endometriosis was not associated with the age of menarche, menstrual cycle length, or onset of menopause (all P FDR > 0.1, Supplementary Table 2). We found a higher prevalence of women with endometriosis who reported difficulties conceiving compared to controls (OR = 3.09, 95% CI = 2.45 – 3.91), though the proportion of women that had been pregnant was similar, i.e., ~60%. Among women with endometriosis, there was no association between the severity of endometriosis and difficulties conceiving ( P FDR > 0.1, Supplementary Table 2). During pregnancy, there was no difference in nausea between women with endometriosis and controls. Table 4. Reproductive characteristics in women with endometriosis versus controls Characteristics n (E/C) Endometriosis Controls P FDR Age of menarche, mean (SD) 512/11,226 13.0 (1.5) 13.2 (1.4) 0.10 Menstrual cycle length, mean (SD) 231/7,048 5.0 (1.7) 5.0 (1.5) 1.00 Age of onset natural menopause, mean (SD) 80/3,606 48.0 (5.7) 49.7 (4.2) 0.27 Age of onset induced menopause, mean (SD) 148/1,507 40.0 (7.5) 43.0 (6.7) <0.001 Tried to conceive ≥6 months w/o success, % 306/6,959 45.4 21.4 <0.001 Have been pregnant, % 308/7,027 58.1 60.7 1.00 Nausea during pregnancy, % 175/4,200 60.6 61.3 1.00 Abbreviations. n = number of participants answered the question; E= women with endometriosis; C = controls; P FDR = false discovery rate The genetic risk of endometriosis was not associated with the onset of induced menopause ( p >0.10). No significant linear association was found between the endometriosis PGS and problems getting pregnant ( p = 0.06). Gastrointestinal symptoms and bowel habits associated with endometriosis We found that women with endometriosis more often reported an irregular defaecation pattern regularity (OR = 1.67, 95% CI = 1.23 - 2.25; Table 5). Moreover, women with endometriosis had more gastrointestinal symptoms, such as abdominal pain, postprandial pain, defaecation pain, and constipation, than the age-matched female controls ( P FDR < 0.05). Those symptoms may be in relation to the higher prevalence of self-reported irritable bowel syndrome among women with endometriosis (OR = 1.95, 95% CI = 1.41– 2.69). Neither the gastrointestinal pain symptoms and defaecation pattern regularity, nor irritable bowel syndrome, were reported more often in cases of stage III/IV endometriosis compared to stage I/II endometriosis ( P FDR > 0.1, Supplementary Table 2). However, constipation occurred more often in women with stage III/IV endometriosis compared to women with stage I/II endometriosis (87.1% versus 71.1%, P FDR = 0.03). We did not find a significant association between severity of endometriosis and self-reported coeliac disease, neither did we find an association with self-reported lactose intolerance. Table 5. Gastrointestinal characteristics in women with endometriosis versus controls Characteristics n (E/C) Endometriosis Controls P FDR Defaecation pattern regularity, irregular, % 301/6,571 18.6 12.2 0.01 Gastrointestinal symptoms Bloating , % 292/6,404 50.3 43.2 0.06 Abdominal rumbling, % 293/6,398 42.7 38.8 0.43 Acid regurgitation , % 293/6,431 14.0 10.8 0.30 Heartburn , % 295/6,442 12.5 11.6 1.00 Lack of appetite , % 294/6,420 6.5 6.3 1.00 Nausea , % 295/6,443 14.2 11.5 0.25 Vomiting , % 293/6,423 1.0 1.3 1.00 Abdominal pain , % 296/6,497 29.7 18.3 <0.001 Pain during food intake , % 296/6,507 2.4 1.0 0.11 Postprandial pain , % 295/6,494 14.9 8.0 <0.001 Defaecation pain , % 295/6,502 15.9 8.4 <0.001 Diarrhoea , % 294/6,483 11.2 10.8 1.00 Constipation , % 290/6,417 20.3 12.5 <0.001 Irritable bowel syndrome, % 250/5,842 20.0 11.4 <0.001 Lactose intolerance, % 258/5.981 5.8 3.3 0.11 Gluten intolerance (celiac disease), % 260/6,010 1.5 0.7 0.40 Abbreviations. n: number of participants answered the question; E: women with endometriosis; C = controls; P FDR = false discovery rate The endometriosis PGS was not associated with defaecation pattern regularity ( p = 0.25), though it did associate with some of the gastrointestinal symptoms, i.e., abdominal pain (OR = 1.22, 95% CI = 1.01-1.47, p = 0.04) and pain during food intake (OR = 2.60, 95% CI = 1.28-5.29, p = 0.01). Furthermore, a doubling in genetic risk of endometriosis was associated with a 1.34 times greater risk of self-reported irritable bowel syndrome (95% CI = 1.06 – 1.69, p = 0.02). Impaired sleep quality in women with endometriosis We found that women with endometriosis suffered more often from insomnia (OR = 1.38, 95% CI = 1.13 – 1.67) and daytime fatigue (OR = 2.10, 95% CI = 1.53– 2.88), but we found no difference in restless legs during sleep compared to controls (Table 6). We did not find an increase in sleep problems related to the severity of endometriosis ( P FDR > 0.1, Supplementary Table 2). Sleep characteristics, such as insomnia, daytime fatigue, and restless legs during sleep, were not associated with the endometriosis PGS. Table 6 . Sleep characteristics in women with endometriosis versus controls Characteristics n (E/C) Endometriosis Controls P Insomnia, % 480/7,505 36.7 28.7 0.02 Daytime fatigue, % 480/7,464 10.4 5.4 <0.001 Restless legs during sleep, % 183/3,986 2.7 1.8 1.00 Abbreviations. n = number of participants answered the question; E= women with endometriosis; C = controls; P FDR = false discovery rate The mental health of those with endometriosis is not affected The impact of health on an individual’s daily life was measured by the SF-12. We did not find any difference between women with endometriosis and their controls on the mental component of SF-12, though we found a lower score of the physical component (OR = 0.27, 95% CI = 0.19 – 0.39) (Table 7). Women with severe endometriosis were not scoring lower on the SF-12 physical component than women with moderate endometriosis (FDR > 0.1, Supplementary Table 2). No difference was found in perceived stress, but the major depression inventory (MDI) score was slightly higher in women with endometriosis (OR = 1.74, 95% CI = 1.10 – 2.65), but they were not more often classified as patients with depression (i.e. MDI score > 20). The SF-12 physical component and MDI score were not associated with the endometriosis PGS. Table 7. Mental health in women with endometriosis versus controls Characteristics n (E/C) Endometriosis Controls P SF-12 mental component, mean (SD) 923/22,153 52.3 (7.7) 52.5 (7.6) 1.00 SF-12 physical component, mean (SD) 923/22,153 53.5 (6.5) 55.0 (5.2) <0.001 Perceived stress scale, mean (SD) 479/7,539 12.3 (5.4) 12.4 (4.9) 1.00 Depression Classification, % 344/9,787 14.0 11.1 1.00 MDI score, mean (SD) 344/9,787 16.3 (4.3) 15.8 (3.9) 0.17 Abbreviations: n = number of participants answered the question; E=women with endometriosis; C= controls; SF-12= 12-item short form survey; MDI= major depression inventory; P FDR = false discovery rate Women with a high genetic risk of endometriosis Given that endometriosis often remains undiagnosed due to its non-specific symptoms, delays presenting to their doctors, and diagnostic challenges, we investigated whether women with a high genetic predisposition to endometriosis exhibit similar characteristics to those with a confirmed diagnosis. Therefore, we analysed individuals in the highest decile of PGS for endometriosis but without an endometriosis diagnosis, focusing on characteristics that significantly differed between these women and controls. Women with a high genetic risk for endometriosis, but without a diagnosis of endometriosis, more closely resembled controls than women with endometriosis diagnosis across most characteristics (Table 8). However, for two characteristics (postprandial pain and insomnia) women with a high genetic risk of endometriosis resembled women with endometriosis diagnosis, with both symptoms occurring more frequently than in age-matched controls. Table 8. Comparing characteristics of women with high PGS for endometriosis without endometriosis diagnosis, with women with endometriosis diagnosis, and with controls. P - value Trait E High PGS C High PGS vs. E High PGS vs. C Age of onset induced menopause, mean (SD) 40.0 (7.6) 43.3 (7.1) 43.0 (6.7) <0.001 0.35 Tried to conceive ≥6 months w/o success, % 45.4 23.8 21.1 <0.001 0.07 Defaecation pattern regularity, irregular, % 18.6 12.7 12.2 0.01 0.67 Abdominal pain, % 29.7 22.4 17.9 0.01 0.004 Postprandial pain, % 14.9 11.3 7.7 0.11 0.001 Defaecation pain, % 15.9 8.6 8.4 <0.001 0.83 Constipation, % 20.3 15.0 12.3 0.03 0.05 Irritable bowel syndrome, % 20.0 13.2 11.2 0.02 0.17 Insomnia, % 36.7 31.8 28.4 0.14 0.02 Daytime fatigue, % 10.4 6.1 5.3 0.01 0.32 SF12 – physical component, mean (SD) 53.5 (6.5) 55.0 (5.3) 54.9 (5.2) <0.001 0.46 Abbreviations: E=women with endometriosis, PGS=Polygenic score, C=controls, Discussion Endometriosis is a heterogeneous, multifactorial, disease that presents many different symptoms and comorbidities 10 . In this study, we showed that women with endometriosis have compromised fertility, more gastrointestinal symptoms, and more sleep disturbances compared to age-matched women without endometriosis. We also showed that the PGS of endometriosis was higher in females with endometriosis than in those without endometriosis and, further, that this genetic burden was associated with gastrointestinal symptoms, potentially suggesting a shared genetic component of endometriosis and those comorbidities. However, in individuals without an endometriosis diagnosis, but with a high genetic burden for endometriosis (top decile PGS), we did not observe the same pattern of comorbidities as we saw in women with an endometriosis diagnosis. Polygenic score predicting endometriosis Previously, two studies have investigated the polygenic score (PGS) of endometrioses 39,40 . Both studies used the 14 genome-wide significant loci that were found associated with endometriosis in, at that time, the largest GWAS of endometriosis available 41 . We calculated the PGS based on the most recent GWAS of endometriosis which increased the number of associated loci 21 . Moreover, in this study, we do not only use the significant SNPs but all available genetic variants, i.e., the whole genome, to capture as much of the genetic variability as possible. This resulted in a more precise (i.e., smaller p-value) but not higher prediction as our area under the receiver operating characteristic curve (AUC = 0.66) was similar to the one found by Kloeve-Mogensen et al . (AUC = 0.64). Where Svensson et al . did not find any difference between PGS and localization, Kloeve-Mogensen et al . found a better prediction for ovarian endometriosis though not significantly different than the other localizations. In our study, we confirm the findings of Kloeve-Mogensen et al , and with the increased sample size we do show a significant higher polygenic burden of endometriosis among women with severe endometriosis (stage III/IV) compared to those with moderate endometriosis (stage I/II). This finding supports the association between a higher genetic burden and greater disease severity 42,43 . Furthermore, we confirm this relationship by showing an elevated polygenic burden in individuals with endometriosis affecting multiple locations. Using the PGS, we investigated whether individuals with a high genetic burden (i.e., top decile PGS, capturing individuals with double risk of endometriosis) but without an endometriosis diagnosis were experiencing similar comorbidities as women diagnosed with endometriosis. While these individuals could provide insight into the consequences of underdiagnosis, in our study they did not show the same patterns of comorbidities as those with a confirmed diagnosis. One explanation is that endometriosis is a highly heterogeneous disease and women with undiagnosed endometriosis might have milder symptoms and did not seek medical attention, or were dismissed when presenting with these symptoms, leading to the perceived lack of a diagnosis and consequently fewer associated comorbidities. Additionally, factors beyond genetics—including hormonal regulation, immune responses, and environmental influences—likely contribute to disease expression and severity, further explaining differences in symptom burden. Another possibility is that the PGS does not fully capture the genetic complexity of endometriosis. While it reflects common genetic variants, endometriosis is a multifactorial disease likely influenced by rare variants, gene-gene, and gene-environment interactions, and epigenetic modifications that current PGS models may not adequately account for. However, we cannot rule out the possibility that these women may develop comorbidities later in life, given that participants in the DBDS cohort are relatively young (mean age of 44.6 years). Endometriosis affects reproductive health One of the most well-established comorbidities of endometriosis is infertility; lesions can cause structural damage to the reproductive organs, alter hormonal signalling, and create an inflammatory environment that can impair fertility 44,45 . The elevated rate of women with endometriosis having challenges conceiving in our otherwise healthy cohort confirms the impact of endometriosis on fertility. It is important to note that among participants who responded 'no' to “tried to conceive ≥6 months w/o success”, we were unable to distinguish between those who conceived within six months and those who had not attempted to conceive. Further, we found that women with endometriosis reported similar age at menarche compared to controls, while others have reported earlier age at menarche among women with endometriosis 46 . Furthermore, contrary to previous findings 47 , we did not find any evidence of shorter menstrual cycles in women with endometriosis, potentially due to the relatively large variation in the data. It has been hypothesized that an earlier, heavier, menstruation is a potential cause of endometriosis 48,49 ; we did not find evidence supporting this hypothesis in our cohort. However, contraceptive use was not considered in this analysis, potentially affecting results by altering menstrual characteristics such as cycle length and bleeding patterns, thereby obscuring natural associations with endometriosis. We observed that women with endometriosis experienced induced menopause three years earlier than women without endometriosis diagnosis, consistent with a recent large multi-cohort study reporting a 1.6-year earlier onset of surgical menopause 50 . In contrast, we did not observe a significant difference in the timing of natural menopause between women with and without endometriosis. Women with endometriosis have more gastrointestinal symptoms Among women with endometriosis, we observed a higher prevalence of irregular stool pattern and constipation. Moreover, women with endometriosis frequently reported gastrointestinal symptoms, including more abdominal pain, postprandial pain, and defaecation pain. This is in accordance with previous findings showing that women with endometriosis have more bowel symptoms than controls, also when no lesions where present on the bowel 51 . Furthermore, we found more constipation among those with stage III-IV endometriosis compared to those with stage I/II endometriosis; note that endometriosis located at the bowel is categorized under ‘ICD10: N80.8 - other endometriosis’ and therefore classified as stage III-IV endometriosis. Further, we found an association between the genetic burden of endometriosis and pain-traits, i.e. abdominal pain and pain during food intake, indicating a genetic overlap between endometriosis and those comorbidities. We found a higher prevalence of self-reported irritable bowel syndrome among women with endometriosis, which is in line with a systematic review, that found a threefold increased risk of irritable bowel syndrome in women with endometriosis 52 . Irritable bowel syndrome and endometriosis have overlap in clinical symptoms, such as abdominal discomfort, pain, and cramping. Therefore, it is difficult to distinguish whether the symptoms are caused by endometriosis or irritable bowel syndrome, thus, misdiagnoses might occur as demonstrated by Nnoaham et al. 53 . Furthermore, we found that the endometriosis PGS was significantly associated with self-reported irritable bowel syndrome, suggesting that individuals with a higher genetic predisposition for endometriosis are also more likely to report irritable bowel syndrome symptoms. While our data indicate an association, the underlying mechanisms remain to be clarified. One possible explanation is shared genetic architecture between the two conditions, which has been supported by prior studies demonstrating significant genetic correlations, such as the work by Yang et al . 54 Though a study among women with celiac disease showed an increased risk of endometriosis 55 , we did not see any increased risk of self-reported celiac disease among women with endometriosis. Sleep and mental health affected by endometriosis It has previously been shown that insomnia and fatigue are more prevalent among women with endometriosis 56,57 , which was also confirmed in our study. We did not see an association between the genetic burden of endometriosis and insomnia or fatigue, indicating that the link between endometriosis and sleep is not due to shared genetic factors, but may be a consequence of increased levels of endometriosis-related pain, inflammation, and associated stress as previously demonstrated 58 . Furthermore, it is well-known that pain can affect sleep 59 . Whereas we did not find a genetic link between gastrointestinal pain and endometriosis, we did not investigate menstrual-related pain, and the latter may explain the link between endometriosis, pain, and sleep. A recently found association between restless legs syndrome and endometriosis was not confirmed in our study 60 . The complexity of endometriosis and its comorbidities can have a major impact on mental health and overall quality of life, with higher levels of depressive and anxiety symptoms 61,62 . We identified a slightly elevated depression score in women with endometriosis compared to the control group, but an assessment using the SF-12 did not indicate a significant impact of endometriosis on mental health, as also demonstrated by Nnoaham et al. . 53 Importantly, the absence of a robust association between endometriosis and mental health in our study could be attributed to the overall good health of our cohort (healthy donor effect), in contrast to a population-based cohort. Moreover, it has previously been shown that women with endometriosis without pelvic pain show no impact on psychological health compared to healthy women 63 . Strengths and limitations The DBDS comprises a mainly healthy cohort, as it is the responsibility of any blood bank to ensure that blood donors are healthy at the time of donating blood. For example, individuals on long-term medical treatment are restricted from donating blood, although the use of contraception or paracetamol are not exclusion criteria. This practice introduces a selection bias, known as the healthy donor effect, which has also been shown in the DBDS cohort 64 . As a result, there is an underrepresentation of physical health issues, together with elevated mental health levels, compared to the general population. Indeed, we observed a prevalence of endometriosis of 1.28%, which is significantly lower than the Danish prevalence of endometriosis diagnosed at hospital of 1.63% in 2017 65 . This suggests that women with endometriosis who are on long-term medications for the severity of their symptoms, are not blood donors. Importantly, many of our findings are consistent with previous studies, showing that endometriosis does not only affect women experiencing severe symptoms, and reminds us that the extent of endometriotic lesions does not necessarily correlate with symptoms, treatment response, or prognosis 66 . We confirm this in our study: only constipation was more prevalent among women with stage III/IV endometriosis than among women with stage I/II endometriosis. Furthermore, the actual estimated prevalence of endometriosis in the general population is ten percent among women in reproductive age 10 . This discrepancy prompts consideration of potential underdiagnosis, a well-known challenge in endometriosis. In this study, results are based on self-reported questionnaires, where participants' responses may be subjective and influenced by their personal perspectives, potentially affecting the precision of the data collected. However, high genetic correlations have been found between self-reported diseases and clinically diagnosed diseases 67 . Furthermore, the responses are limited by potential recall bias, influencing the accuracy of participants' recollection of past events or experiences. In the case of self-reported diseases, and in case of diseases with overlapping symptoms such as endometriosis and irritable bowel syndrome, we acknowledge the potential for misclassification bias. The potential for confounding variables, sampling bias, and the challenge of establishing a clear temporal relationship further contribute to the complexity of interpreting our results. This study is a retrospective study, and we defined the participant as ‘a case’ when the questionnaire was filled in after a diagnosis of endometriosis. As there is a substantial delay 14–16 in diagnosing endometriosis, this may affect our results in different ways. Firstly, the delayed diagnosis may skew the representation of endometriosis severity, potentially underrepresenting milder cases where individuals have adapted to the disease over time, which affects the generalizability of our results across the entire spectrum of endometriosis severity. Secondly, delayed diagnosis affects the temporal aspect of comorbidity associations. Prolonged exposure to endometriosis without early intervention may contribute to the development of certain comorbidities 18,53,68 . Therefore, our findings not only highlight the inherent association between endometriosis and comorbidities but also underscore the impact of delayed diagnosis on these observed relationships. Lastly, both the delay between symptom onset and diagnosis, and the subsequent delay in initiating treatment, may act as confounding factors by influencing the severity or progression of comorbidities. For instance, longer periods without appropriate management may allow comorbid conditions to develop or worsen, thereby exaggerating their association with endometriosis in our data. Variations in treatment regimens and their effectiveness over the extended life course of the disease may influence the prevalence and severity of associated comorbidities in the endometriosis group, necessitating a cautious interpretation of these relationships. Unfortunately, our sample size did not provide enough statistical power to investigate the effect of treatment after receiving a diagnosis. Conclusions Endometriosis is a heterogeneous, multifactorial disease characterized by diverse symptoms and comorbidities. In this study, we demonstrated that women with endometriosis experience compromised fertility, increased gastrointestinal symptoms, and more frequent sleep disturbances compared to age-matched female controls. We also found that the PGS for endometriosis was higher in women with a diagnosis than in those without, and that this genetic burden was associated with gastrointestinal symptoms, suggesting a potential shared genetic basis. However, women without a diagnosis but with a high genetic predisposition for endometriosis did not exhibit the same broad pattern of comorbidities as seen in diagnosed cases. Our study contributes valuable insights, as well as confirmation of results from previous studies in different cohorts, into the complex interplay between endometriosis and comorbidities, underscoring the need for studying and treating endometriosis as the heterogenous disease that it is. Abbreviations DBDS: Danish Blood Donor Study PGS: Polygenic score OR: Odds ratio GWAS: genome-wide association studies SF12: Short Form Health Survey 12 DNPR: Danish National Patient Registry PCs: principal components LD: linkage disequilibrium PCS: physical component summary score MCS: mental component summary score PSS: Cohen’s Perceived Stress Scale MDI: Major Depression Inventory AUC: area under the curve FDR: False Discovery Rate SD: standard deviation Declarations Ethical statements. The DBDS has the necessary permissions and approval from the Danish Data Protection Agency (2007-58-0015) and the Scientific Ethical Committee system (M-20090237). All participants provided informed oral and written consent to participate. Availability of data and materials Data cannot be made publicly available, but the DBDS is open for collaboration. Enquiries regarding collaboration can be addressed to the DBDS steering committee. Potential collaborators are encouraged to find additional information and contact details on our homepage www.dbds.dk. Conflict of interest CLH received research support from Novo Nordisk Foundataion (grant no. NNF22OC0074080) and lecture fees from BMS, Janssen, Tillotts, Servier, and Merck. All other authors do not report any conflicts of interest. Funding This work was supported by a grant from the Novo Nordisk Foundation to MN (grant number NNF21OC0071050). This article is part of the project Finding Endometriosis using Machine Learning (FEMaLe/101017562), which has received funding from the European Union's Horizon 2020 research and innovation program. The Danish Blood Donor Study (DBDS) is funded by an annual grant from Bio- and Genome Bank Denmark. The initiation of DBDS was supported by the Danish Administrative Regions (02/2611) and the Danish Council for Independent Research (09–069412). Additionally, the DBDS is funded by the Novo Nordisk Foundation (NNF23OC0082015, NNF17OC0027864, and NNF17OC0027594). Author contributions: LK performed the formal analysis, developed the methodology, created the visualizations, and was the lead author of the original draft. DR, LH, KEH, UBK, JLB, and HSN contributed to writing, review, and editing of the manuscript. JTB, MTB, NB, CE, BAJ, BDK, CM, SM, SRO, OBP, ES, HU, AKG, CLH, VS, and KS provided resources and contributed to data acquisition. KB and PDR contributed to the methodology and to writing, review, and editing of the manuscript. MN was responsible for the conceptualisation of the study, acquisition of funding, development of methodology, and supervision of the writing and review process. All authors have read, reviewed, and approved the final version of the manuscript. Acknowledgements We thank the staff of the Danish blood banks and the Danish blood donors for their participation, enabling us to carry out this research. 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Taylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. The Lancet 2021; 397: 839–852. Additional Declarations Competing interest reported. CLH received research support from Novo Nordisk Foundataion (grant no. NNF22OC0074080) and lecture fees from BMS, Janssen, Tillotts, Servier, and Merck. All other authors do not report any conflicts of interest. Supplementary Files consortiumauthorsDBDSGC.xlsx SupplTable1.xlsx Supplementary Table 1. All questions used in this study. SupplTable2.xlsx Supplementary Table 2. Associations between the severity of endometriosis and comorbidities. Cite Share Download PDF Status: Published Journal Publication published 14 Oct, 2025 Read the published version in BMC Medicine → Version 1 posted Editorial decision: Revision requested 23 Jun, 2025 Reviews received at journal 20 Jun, 2025 Reviews received at journal 16 Jun, 2025 Reviewers agreed at journal 14 Jun, 2025 Reviewers agreed at journal 12 Jun, 2025 Reviewers invited by journal 16 May, 2025 Editor assigned by journal 09 May, 2025 Submission checks completed at journal 09 May, 2025 First submitted to journal 08 May, 2025 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. 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. 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Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bitten","middleName":"","lastName":"Aagaard","suffix":""},{"id":465727720,"identity":"b4f99992-9817-47c1-86ef-3a33c0b9fcd9","order_by":11,"name":"Bertram Dalskov Kjerulff","email":"","orcid":"","institution":"Aarhus University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Bertram","middleName":"Dalskov","lastName":"Kjerulff","suffix":""},{"id":465727721,"identity":"3b0544ff-ba57-4b58-94fb-ca2bf5ea3797","order_by":12,"name":"Christina Mikkelsen","email":"","orcid":"","institution":"Copenhagen University Hospital - Rigshospitalet","correspondingAuthor":false,"prefix":"","firstName":"Christina","middleName":"","lastName":"Mikkelsen","suffix":""},{"id":465727723,"identity":"4d76b19e-de51-4ddc-8da7-52f9c379125e","order_by":13,"name":"Susan Mikkelsen","email":"","orcid":"","institution":"Aarhus University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Susan","middleName":"","lastName":"Mikkelsen","suffix":""},{"id":465727724,"identity":"42da646b-1aca-4445-b6f5-1356379494ae","order_by":14,"name":"Sisse Rye Ostrowski","email":"","orcid":"","institution":"Copenhagen University Hospital - Rigshospitalet","correspondingAuthor":false,"prefix":"","firstName":"Sisse","middleName":"Rye","lastName":"Ostrowski","suffix":""},{"id":465727725,"identity":"26919652-02f2-4d6a-898f-1d074eacfcb0","order_by":15,"name":"Ole Birger Pedersen","email":"","orcid":"","institution":"Zealand University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Ole","middleName":"Birger","lastName":"Pedersen","suffix":""},{"id":465727726,"identity":"fd4b0807-d6ae-49b9-8994-39c043df1452","order_by":16,"name":"Erik Sørensen","email":"","orcid":"","institution":"Copenhagen University Hospital - Rigshospitalet","correspondingAuthor":false,"prefix":"","firstName":"Erik","middleName":"","lastName":"Sørensen","suffix":""},{"id":465727727,"identity":"3ae964e5-421b-4849-9eaf-aea1f21364df","order_by":17,"name":"Henrik Ullum","email":"","orcid":"","institution":"Statens Serum Institut","correspondingAuthor":false,"prefix":"","firstName":"Henrik","middleName":"","lastName":"Ullum","suffix":""},{"id":465727728,"identity":"0857bfe0-8036-4c22-b59d-4d0cbedf8a77","order_by":18,"name":"Anne Karmisholt Grosen","email":"","orcid":"","institution":"Aarhus University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Anne","middleName":"Karmisholt","lastName":"Grosen","suffix":""},{"id":465727730,"identity":"52610832-e824-4f65-8c7b-acddbff0f445","order_by":19,"name":"Christian Lodberg Hvas","email":"","orcid":"","institution":"Aarhus University Hospital","correspondingAuthor":false,"prefix":"","firstName":"Christian","middleName":"Lodberg","lastName":"Hvas","suffix":""},{"id":465727738,"identity":"f205422b-620e-444f-a14f-b4dfed4134c4","order_by":20,"name":"Valgerdur Steinthorsdottir","email":"","orcid":"","institution":"deCODE Genetics (Iceland)","correspondingAuthor":false,"prefix":"","firstName":"Valgerdur","middleName":"","lastName":"Steinthorsdottir","suffix":""},{"id":465727740,"identity":"b360cf51-69df-4e64-b089-8202439221dd","order_by":21,"name":"Kari Stefansson","email":"","orcid":"","institution":"deCODE Genetics (Iceland)","correspondingAuthor":false,"prefix":"","firstName":"Kari","middleName":"","lastName":"Stefansson","suffix":""},{"id":465727741,"identity":"6732853a-5e1b-47f2-9a46-be158f1f9a37","order_by":22,"name":"Karina Banasik","email":"","orcid":"","institution":"Technical University Hospital of Greater Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Karina","middleName":"","lastName":"Banasik","suffix":""},{"id":465727745,"identity":"e9380e91-25fb-47fb-b411-28cb136e6974","order_by":23,"name":"Palle Duun Rohde","email":"","orcid":"","institution":"Aalborg University","correspondingAuthor":false,"prefix":"","firstName":"Palle","middleName":"Duun","lastName":"Rohde","suffix":""},{"id":465727751,"identity":"190a866c-00e8-486b-b28e-01e7df696e41","order_by":24,"name":"Henriette Svarre Nielsen","email":"","orcid":"","institution":"Technical University Hospital of Greater Copenhagen","correspondingAuthor":false,"prefix":"","firstName":"Henriette","middleName":"Svarre","lastName":"Nielsen","suffix":""},{"id":465727752,"identity":"2bc6eaf2-aecb-4dd1-83a6-047dc76ed07a","order_by":25,"name":"Mette Nyegaard","email":"","orcid":"","institution":"Aalborg University","correspondingAuthor":false,"prefix":"","firstName":"Mette","middleName":"","lastName":"Nyegaard","suffix":""}],"badges":[],"createdAt":"2025-05-08 11:53:12","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6620337/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6620337/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12916-025-04398-z","type":"published","date":"2025-10-14T15:57:26+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":83983553,"identity":"316a817f-c03b-478d-b581-83f2b5fb583f","added_by":"auto","created_at":"2025-06-05 10:32:17","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":151943,"visible":true,"origin":"","legend":"\u003cp\u003eSummary of findings of comparing women with endometriosis with age-matched controls.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/84f02d25dc9b0c470dfb7649.png"},{"id":83983551,"identity":"4155683d-b63b-4d53-937a-38d9d307a8db","added_by":"auto","created_at":"2025-06-05 10:32:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":78533,"visible":true,"origin":"","legend":"\u003cp\u003eA) Density plot of the endometriosis polygenic score (PGS) in healthyfemales, patients with moderate endometriosis, and patients with severe endometriosis, B) PGS divided into deciles and the proportion of cases are counted per decile (numbers of controls are written above the bars, number of cases written in the bars), and C) for each PGS decile, the odds ratio (OR) for endometriosis was estimated (error bars indicate standard error of the estimate; reference decile was set to decile 5).\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/29b9bd4a9991522693851b79.png"},{"id":93957010,"identity":"093382ca-b80f-478c-a0bb-efd5174eaae0","added_by":"auto","created_at":"2025-10-20 16:12:46","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1773864,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/72e0eaa0-74d0-4b6a-b7e9-c586405b8feb.pdf"},{"id":83984275,"identity":"8a8b2243-1cf5-4288-87b5-6a8d6c0f2ece","added_by":"auto","created_at":"2025-06-05 10:40:17","extension":"xlsx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":15388,"visible":true,"origin":"","legend":"","description":"","filename":"consortiumauthorsDBDSGC.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/71832f0dd334cfa88a2e7a8f.xlsx"},{"id":83983013,"identity":"671e9081-4207-4453-8cf2-7dd2407cc3c0","added_by":"auto","created_at":"2025-06-05 10:24:17","extension":"xlsx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":13875,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 1. \u003c/strong\u003eAll questions used in this study.\u003c/p\u003e","description":"","filename":"SupplTable1.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/29517e7637f8b06983aef4bc.xlsx"},{"id":83983014,"identity":"c7b2af0c-a6cd-45ef-a528-4b48f57e2513","added_by":"auto","created_at":"2025-06-05 10:24:17","extension":"xlsx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":11215,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 2. \u003c/strong\u003eAssociations between the severity of endometriosis and comorbidities.\u003c/p\u003e","description":"","filename":"SupplTable2.xlsx","url":"https://assets-eu.researchsquare.com/files/rs-6620337/v1/c3d205547a5f3925c2726a4f.xlsx"}],"financialInterests":"Competing interest reported. CLH received research support from Novo Nordisk Foundataion (grant no. NNF22OC0074080) and lecture fees from BMS, Janssen, Tillotts, Servier, and Merck. All other authors do not report any conflicts of interest.","formattedTitle":"The burden of endometriosis on quality of life in Danish blood donors","fulltext":[{"header":"Background","content":"\u003cp\u003eEndometriosis is a complex condition that imposes a substantial economic burden \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e,\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. It is estimated to affect approximately 10% of reproductive-age women worldwide, although prevalence varies depending on diagnostic criteria and population characteristics \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Endometriosis extends far beyond its primary manifestation of endometrial-like tissue outside the uterus to a large range of comorbidities, such as infertility, persistent abdominal pain, gastrointestinal complications, migraine, and challenges related to mental health \u003csup\u003e\u003cspan additionalcitationids=\"CR6 CR7 CR8 CR9\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. Endometriosis is widely underdiagnosed \u003csup\u003e\u003cspan additionalcitationids=\"CR12\" citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e, with a diagnostic delay of 4 to 10 years \u003csup\u003e\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e which leads to delayed treatment and prolonged patient suffering \u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e,\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e. This diagnostic delay not only exacerbates disease progression but may also contribute to an increased burden of comorbid conditions. Understanding the relationship between endometriosis and its comorbidities is crucial for enabling early detection, improving patient outcomes, and build comprehensive management strategies.\u003c/p\u003e \u003cp\u003eAlthough the exact aetiology of endometriosis is still not fully understood, substantial evidence suggests a significant genetic component in the risk of developing the condition, with an estimated heritability of around 50% \u003csup\u003e19,20\u003c/sup\u003e. Genome-wide association studies (GWAS) have identified 42 common genetic loci associated with the risk of endometriosis \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e with moderate to small effect sizes. Due to the moderate to small effect sizes, common in complex diseases \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, there is considerable interest in consolidating the impacts of multiple genetic risk variants into a combined score. A commonly employed scoring method involves calculating the sum of risk alleles, with each single nucleotide variant weighted by its GWAS effect size \u0026ndash; known as a polygenic score (PGS) \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e,\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Because the PGS has a theoretical relationship with the genetic liability model of polygenic diseases it has led to widespread use of PGS in biomedical research \u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. We hypothesize that the observed comorbidities are intricately linked to the genetic burden of endometriosis.\u003c/p\u003e \u003cp\u003eIn this study, we investigate 37 comorbidities of endometriosis in up to 24,605 individuals participating in the Danish Blood Donor Study (DBDS) \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. By constructing a genome-wide PGS for endometriosis, we assess to what degree the genetic burden of endometriosis was associated with comorbidities of endometriosis. This approach enhances our understanding of the impact of endometriosis on quality of life and the potential association of endometriosis with genetic factors.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e \u003cb\u003eStudy population\u003c/b\u003e. From March 2010 to December 2022 voluntary blood donors were recruited as part of the Danish Blood Donor Study (DBDS), an ongoing prospective population-based research cohort \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Eligible participants were aged 18\u0026ndash;67 years and weighing\u0026thinsp;\u0026gt;\u0026thinsp;50 kg. Blood donors are subject to strict eligibility criteria as defined by the Transfusion Medicine Standards (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://dski.dk/gaeldende-version/\u003c/span\u003e\u003cspan address=\"https://dski.dk/gaeldende-version/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e). Participating blood donors completed between one to four different questionnaires during the recruitment period. The first version was a paper-based questionnaire, whilst the following three were digital questionnaires. Questionnaires covered questions on self-experienced physical and mental health (including the Short Form Health Survey 12 [SF-12]\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e), smoking habits, sleep patterns, allergies, attention-deficit/hyperactivity disorder (ADHD), migraine, depression, pregnancy, gastrointestinal symptoms, and many other health-related conditions.\u003c/p\u003e \u003cp\u003e \u003cb\u003eDiagnosis of endometriosis.\u003c/b\u003e The Danish National Patient Registry (DNPR) contains data on all in- and outpatients discharged from Danish hospitals since 1977 and, since 2002, it also includes records from Danish private hospitals. An endometriosis diagnosis was defined based on the presence of any of the codes: ICD-8 codes 62.530 and 62.532\u0026ndash;62.539 (\u0026lt;\u0026thinsp;1994) and ICD-10 codes N80.1-N80.9 (\u0026ge;\u0026thinsp;1994) in the DNPR, regardless of surgical or histologic verification. Adenomyosis diagnoses (ICD8: 62531, ICD10: N80.0) were not included. The date of diagnosis was based on the hospital admission date for the first endometriosis diagnosis. For each questionnaire, a participant was counted as an endometriosis-case when, at the time of filling out the questionnaire, the individual had a diagnosis of endometriosis in DNPR. Diagnoses were subdivided into \u0026lsquo;deep endometriosis\u0026rsquo; (ICD8: 62535, 62536; ICD10: N80.4, N80.5), \u0026lsquo;ovarian endometriosis \u0026lsquo;(ICD8: 62530; ICD10: N80.1), \u0026lsquo;peritoneal endometriosis\u0026rsquo; (ICD8: 62532, 62533; ICD10: N80.2, N80.3), and \u0026lsquo;other endometriosis\u0026rsquo; (ICD8: 62537, 62538; ICD10: N80.6, N80.8, N80.9). Severity of endometriosis was divided into severe (i.e. stage III/IV endometriosis including \u0026lsquo;deep\u0026rsquo; and/or \u0026lsquo;ovarian\u0026rsquo;- endometriosis) and moderate (i.e., stage I/II endometriosis including \u0026lsquo;peritoneal\u0026rsquo; and/or \u0026lsquo;other\u0026rsquo;- endometriosis according to the r-ASRM score) \u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eAge-matching.\u003c/b\u003e Female blood donors with an endometriosis diagnosis were significantly older than females without endometriosis (45.7 \u003cem\u003eversus\u003c/em\u003e 44.6 years, \u003cem\u003ep\u003c/em\u003e\u0026thinsp;=\u0026thinsp;2.28\u0026times;10\u003csup\u003e\u0026minus;\u0026thinsp;3\u003c/sup\u003e). Therefore, for each questionnaire, an age-matched female study population was selected from the DBDS cohort, with a case:control ratio of ~\u0026thinsp;1:25 (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At the time of filling in the respective questionnaires, the \u0026lsquo;case\u0026rsquo; had to have an endometriosis diagnosis; \u0026lsquo;controls\u0026rsquo; were not diagnosed with endometriosis at any point throughout the complete study period (8 March 1977\u0026ndash;9 November 2022) and all had genetic data available.\u003c/p\u003e \u003cp\u003e \u003cb\u003eGenetic data.\u003c/b\u003e The majority of the DBDS participants have genetic information available (\u003cem\u003en\u003c/em\u003e\u0026thinsp;=\u0026thinsp;100,146), which established the DBDS Genomic Cohort \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. A total of 649 women with endometriosis and all 23,652 age-matched female controls had genetic information available (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). At inclusion, a blood sample for DNA analyses was collected and saved in the biobank. DNA genotyping of the DBDS samples was obtained at deCODE Genetics using the Global Screening Array by Illumina. The raw genotype data was processed at deCODE genetics simultaneously for genotype calling, quality control and genotype imputation using an in-house reference panel consisting of UK 1KG phase 3, HapMap reference and an in-house dataset of \u0026gt;\u0026thinsp;6,000 Danish whole genome sequences \u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Genetic principal components (PCs) for the study cohort were calculated on a reduced dataset of 30,966 genetic variants by linkage disequilibrium (LD) pruning using PLINK \u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. PCs were calculated using flashPCA \u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e and the resulting PCs were included in subsequent analyses to account for population stratification. Any related individuals were removed from the data (up to second degree relatives) to avoid inflated predictions in subsequent analysis.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eOverview of questionnaires and a breakdown of the number of individuals (\u003cem\u003en\u003c/em\u003e) with questionnaire (Q) and genetic (G) data available\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"6\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eQuestionnaire\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eTime\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c4\" namest=\"c3\"\u003e \u003cp\u003e\u003cem\u003en\u003c/em\u003e\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eEndometriosis (Q|G)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eControl\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBDS1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e03/2010\u0026ndash;01/2015\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e526|471\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e11,572\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBDS2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e05/2015\u0026ndash;06/2018\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e350|266\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e10,016\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBDS3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e06/2018\u0026ndash;03/2020\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e308|190\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e7,051\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDBDS4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e11/2020\u0026ndash;11/2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e301|153\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e6,575\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal (unique)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e03/2010\u0026ndash;11/2022\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e953|649\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e23,652\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c6\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colspan=\"6\" nameend=\"c6\" namest=\"c1\"\u003e \u003cp\u003e\u003csup\u003e*\u003c/sup\u003e\u003cem\u003en\u003c/em\u003e: count, Q: questionnaire data available, G: genetic information available. Selected controls all had both questionnaire and genetic data available.\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cb\u003eAssessing comorbidities.\u003c/b\u003e All questions used in this study are presented in Supplementary Table\u0026nbsp;1; participants only received the Danish question. Questionnaire data was pre-processed at question level by excluding individuals who answered, \u0026ldquo;Do not know\u0026rdquo;. Several questions were part of a scoring system, where multiple questions were combined into a single scale. Insomnia was defined as experiencing at least one of three symptoms\u0026thinsp;\u0026ge;\u0026thinsp;3 times per week: (1) difficulty falling asleep within 30 minutes, (2) waking up too early and unable to fall back asleep, or (3) woken up during the night or early morning. Daytime fatigue was defined as experiencing at least one of three symptoms\u0026thinsp;\u0026ge;\u0026thinsp;3 times per week: (1) extreme tiredness during the day, (2) an irresistible urge to sleep at work/school, and (3) an irresistible urge to sleep during spare time. Restlessness in legs during sleep was identified when participants reported experiencing restless legs\u0026thinsp;\u0026ge;\u0026thinsp;3 times per week. Physical and mental health status was measured using the 12-item Short Form Health Survey (SF-12), which yields two composite scores: the physical component summary score (PCS) and the mental component summary score (MCS) \u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Scores were calculated using weighted item endorsements, yielding values between 0 and 100, with higher scores reflecting better quality of life \u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e. Perceived stress was measured using the 10-item Cohen\u0026rsquo;s Perceived Stress Scale (PSS) \u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e. The questions were answered on a 5-point Likert scale, asking the respondents to indicate how often they experience a specific stress symptom ranging from \u0026ldquo;0\u0026thinsp;=\u0026thinsp;never\u0026rdquo; to \u0026ldquo;4\u0026thinsp;=\u0026thinsp;very often\u0026rdquo;, resulting in a score ranging from 0 to 40. Depression was measured using the Major Depression Inventory (MDI): a validated self-report questionnaire of 10 items ranging from 0 to 5 \u003csup\u003e35,36\u003c/sup\u003e. The MDI score was calculated as the sum of all 10 items, including only the item with the highest score out of item 8a and 8b, and similarly the one with the highest score out of item 10a and 10b. Depression was analysed both on a continuous scale (MDI score) and classification of depression using a cut-off of \u0026gt;\u0026thinsp;20.\u003c/p\u003e \u003cp\u003eAs participants might have donated blood more than once during the 12-year period they may have participated in multiple questionnaires. When a question was asked more than once (e.g., smoking behaviour and body mass index), the answer in the most recent questionnaire was used in this study. For women with endometriosis, the most recent questionnaire after having received an endometriosis diagnosis was used.\u003c/p\u003e \u003cp\u003e\u003cb\u003ePolygenic score for endometriosis.\u003c/b\u003e The endometriosis PGS, representing the genetic burden of endometriosis, was constructed utilising GWAS summary data from the most recent endometriosis meta-GWAS \u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e, where cases and controls from the DBDS cohort and the 23andMe cohort were excluded to avoid sample overlap. The endometriosis PGS was calculated using LDpred2 software \u003csup\u003e\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e\u003c/sup\u003e using the auto option with default settings. The endometriosis PGS was standardized to a mean of zero and standard deviation of 1, and when used to measure the prediction accuracy for the comorbidities, the endometriosis PGS was rescaled to a mean of zero and one unit standard deviation corresponding to a twofold genetic increased risk for endometriosis in the target population; this was done by subtracting the mean PGS from each individuals\u0026rsquo; PGS and then multiplying by log(OR)/log(2), where the odds ratio (OR) was obtained from the model predicting endometriosis (see below). To investigate whether participants with a high genetic burden for endometriosis exhibit similar comorbidities as women diagnosed with endometriosis, we selected a subset of controls whose PGS values were in the top decile of the PGS distribution.\u003c/p\u003e \u003cp\u003e\u003cb\u003eStatistical analyses.\u003c/b\u003e Differences in comorbidities between those diagnosed with endometriosis and female participants without were compared using Student's t-tests (continuous traits), \u003cspan class=\"InlineEquation\"\u003e\u003cspan class=\"mathinline\"\u003e\\(\\:{\\chi\\:}^{2}\\)\u003c/span\u003e\u003c/span\u003e-squared test (binomial traits), or Wilcoxon signed-rank test (ordinal traits). All analyses were corrected for age and blood donation region (i.e. the region of Denmark where the participant donated blood), as we found significant differences in endometriosis diagnosis between the different regions of Denmark in concordance with a previous study (Illum et al., 2022). Resulting \u003cem\u003ep\u003c/em\u003e-values were corrected for multiple testing, based on the number of tests performed (n\u0026thinsp;=\u0026thinsp;37) using the False Discovery Rate (FDR) \u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Statistical differences between endometriosis cases and controls were determined significant when \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.05. Further, we investigated whether there were differences in comorbidities between women with stage I/II endometriosis compared to women with stage III/IV endometriosis using the same model as described above. Similar, resulting p-values were corrected for multiple testing using the FDR, and determined significant when \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.05.\u003c/p\u003e \u003cp\u003eOnly comorbidities that were significantly associated with endometriosis were subsequently associated with the endometriosis PGS using a logistic regression including region and the first five genetic PCs as covariates. The discriminative ability of the PGS was determined using the area under the receiver operating curve (AUC). Comorbidities that displayed an association with endometriosis PGS of \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.05 were considered significant. Significant predictions were presented as odds ratios with 95% confidence intervals, using the rescaled PGS, i.e., one standard deviation of the PGS corresponds to a twofold genetic increased risk for endometriosis. All statistical analyses were performed in R (v4.0.0).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eFrom 24,605 females selected from the DBDS cohort for this study, 953 females were diagnosed with endometriosis at the time of filling in (one of) the questionnaires. A summary of our findings is presented in Figure 1. The majority of women with endometriosis were diagnosed with one morphological location of endometriosis (\u003cem\u003en\u003c/em\u003e=521), while 225 were diagnosed with endometriosis in two locations, and 178 with three or more locations. The remaining 29 were not diagnosed with a specific endometriosis location. Of the 953, 534 (56%) were categorized as moderate endometriosis (stage I/II) and 419 (44%) as severe endometriosis (stage III/IV).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGeneral characteristics of women with endometriosis\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOn average, endometriosis was diagnosed at the age of 33.0 (SD = 8.3) years. Before age-matching, we found a prevalence proportion for endometriosis of 1.28%. Even though the prevalence proportions differed by region of Denmark (\u003cem\u003ep\u003c/em\u003e \u0026lt;0.001), we did not see a significant difference in age at diagnosis between the regions (\u003cem\u003ep\u003c/em\u003e = 0.05). Women diagnosed with endometriosis had similar body mass index (BMI), standing height, and waist circumference as the female controls (Table 2), and there was no difference in frequency of smoking (or smoking in the childhood home) observed between women with endometriosis and their aged-matched controls (Table 2). \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u0026nbsp;\u003c/strong\u003eDescriptive statistics of the cohort\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"606\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(E/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eBMI, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e941/23,487\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e25.9 (4.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e25.6 (4.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eHeight, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e951/23,606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e169.1 (6.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e168.8 (6.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eWaist circumference, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e482/10,526\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e87.3 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e86.0 (11.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eSmoking, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e950/18,517\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e15.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e15.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 237px;\"\u003e\n \u003cp\u003eSmoking in childhood home, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 93px;\"\u003e\n \u003cp\u003e524/11,357\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e74.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e65.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eGenetic risk of endometriosis predicts endometriosis and its severity\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DBDS genomic cohort included 649 endometriosis cases and 23,652 age-matched controls. The average standardized endometriosis PGS was significantly higher in women with endometriosis than in controls (Figure 2A), with an OR for endometriosis of 1.43 (95% CI = 1.32 \u0026ndash; 1.55) and AUC of 0.66 (\u003cem\u003ep\u003c/em\u003e \u0026lt;0.001). The age of endometriosis diagnosis was not significantly associated with the endometriosis PGS (\u003cem\u003ep\u003c/em\u003e = 0.99). The endometriosis PGS was higher in all endometriosis subtypes, except for \u0026lsquo;\u003cem\u003eother\u0026rsquo;\u003c/em\u003e (\u003cem\u003ep\u003c/em\u003e = 0.55), compared to the controls (Table 3) and was higher among women with stage III/IV endometriosis than women with stage I/II endometriosis (\u003cem\u003ep\u003c/em\u003e = 2.11\u0026times;10\u003csup\u003e-3\u003c/sup\u003e). The endometriosis PGS was also higher in women with endometriosis at multiple locations (OR = 1.30, 95% CI = 1.14 - 1.49, \u003cem\u003ep\u003c/em\u003e \u0026lt; 0.001) Furthermore, individuals in the top 10 percent of PGS had more than double the risk for endometriosis compared to individuals with a median PGS (Figure 2B-C).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Prediction of endometriosis at different locations using the polygenic score (PGS) of endometrioses.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"584\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003csup\u003e*\u003c/sup\u003e\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePGS\u0026nbsp;\u003c/strong\u003e(mean [SD])\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAUC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis (any)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e649\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.35 (1.01)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.66\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Deep\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e78\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.51 (1.07)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.75\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Ovarian\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e253\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.49 (0.99)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.68\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Peritoneal\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e215\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.47 (0.98)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.69\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 188px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; Other\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 86px;\"\u003e\n \u003cp\u003e396\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e0.36 (1.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 88px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 95px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 584px;\"\u003e\n \u003cp\u003eAbbreviations: \u003cem\u003en\u003c/em\u003e = number of cases; PGS = standardized polygenic score; AUC = area under the receiver operating characteristic curve; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = false discovery rate.\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 584px;\"\u003e\n \u003cp\u003e\u003csup\u003e*\u003c/sup\u003eTested against all (n=23,652) controls\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eReproductive health in women with endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe reproductive health of women with endometriosis was different to the aged-matched female controls (Table 4). Women with endometriosis reported no earlier age at menarche compared to controls, neither did we find a difference in menstrual cycle length. Furthermore, among women who entered menopause at the time of filling out the questionnaire, we found an earlier age of induced onset of menopause (three years earlier), but not in natural menopause. The severity of endometriosis was not associated with the age of menarche, menstrual cycle length, or onset of menopause (all \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.1, Supplementary Table 2). We found a higher prevalence of women with endometriosis who reported difficulties conceiving compared to controls (OR = 3.09, 95% CI = 2.45 \u0026ndash; 3.91), though the proportion of women that had been pregnant was similar, i.e., ~60%. Among women with endometriosis, there was no association between the severity of endometriosis and difficulties conceiving (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.1, Supplementary Table 2). During pregnancy, there was no difference in nausea between women with endometriosis and controls. \u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 4.\u003c/strong\u003e Reproductive characteristics in women with endometriosis versus controls\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"696\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003e\u0026nbsp;\u003c/sub\u003e\u003c/strong\u003e\u003cstrong\u003e(E/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eAge of menarche, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e512/11,226\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e13.0 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e13.2 (1.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eMenstrual cycle length, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e231/7,048\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e5.0 (1.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e5.0 (1.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eAge of onset natural menopause, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e80/3,606\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e48.0 (5.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e49.7 (4.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e0.27\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eAge of onset induced menopause, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e148/1,507\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e40.0 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e43.0 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eTried to conceive \u0026ge;6 months w/o success, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e306/6,959\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e45.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e21.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eHave been pregnant, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e308/7,027\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e58.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e60.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 315px;\"\u003e\n \u003cp\u003eNausea during pregnancy, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e175/4,200\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e60.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e61.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 695px;\"\u003e\n \u003cp\u003eAbbreviations. \u003cem\u003en\u003c/em\u003e= number of participants answered the question; E= women with endometriosis; C = controls; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = false discovery rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe genetic risk of endometriosis was not associated with the onset of induced menopause (\u003cem\u003ep\u003c/em\u003e \u0026gt;0.10). No significant linear association was found between the endometriosis PGS and problems getting pregnant (\u003cem\u003ep\u003c/em\u003e = 0.06). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGastrointestinal symptoms and bowel habits associated with endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found that women with endometriosis more often reported an irregular defaecation pattern regularity (OR = 1.67, 95% CI = 1.23 - 2.25; Table 5). Moreover, women with endometriosis had more gastrointestinal symptoms, such as abdominal pain, postprandial pain, defaecation pain, and constipation, than the age-matched female controls (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026lt; 0.05). Those symptoms may be in relation to the higher prevalence of self-reported irritable bowel syndrome among women with endometriosis (OR = 1.95, 95% CI = 1.41\u0026ndash; 2.69). Neither the gastrointestinal pain symptoms and defaecation pattern regularity, nor irritable bowel syndrome, were reported more often in cases of stage III/IV endometriosis compared to stage I/II endometriosis (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.1, Supplementary Table 2). However, constipation occurred more often in women with stage III/IV endometriosis compared to women with stage I/II endometriosis (87.1% versus 71.1%, \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = 0.03). We did not find a significant association between severity of endometriosis and self-reported coeliac disease, neither did we find an association with self-reported lactose intolerance.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 5.\u0026nbsp;\u003c/strong\u003eGastrointestinal characteristics\u0026nbsp;in women with endometriosis versus controls\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"665\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(E/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u003csub\u003eFDR\u003c/sub\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eDefaecation pattern regularity, irregular, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e301/6,571\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e18.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eGastrointestinal symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eBloating\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e292/6,404\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e50.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e43.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eAbdominal rumbling,\u003c/em\u003e %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e293/6,398\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e42.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e38.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.43\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eAcid regurgitation\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e293/6,431\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.30\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eHeartburn\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e295/6,442\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e11.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eLack of appetite\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e294/6,420\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e6.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e6.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eNausea\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e295/6,443\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e11.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eVomiting\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e293/6,423\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eAbdominal pain\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e296/6,497\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e29.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e18.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003ePain during food intake\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e296/6,507\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e2.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003ePostprandial pain\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e295/6,494\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e8.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eDefaecation pain\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e295/6,502\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e15.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eDiarrhoea\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e294/6,483\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e11.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 194px;\"\u003e\n \u003cp\u003e\u003cem\u003eConstipation\u003c/em\u003e, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e290/6,417\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e12.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eIrritable bowel syndrome, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e250/5,842\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e11.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eLactose intolerance, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e258/5.981\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e5.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e3.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 302px;\"\u003e\n \u003cp\u003eGluten intolerance (celiac disease), %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e260/6,010\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 113px;\"\u003e\n \u003cp\u003e1.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\" style=\"width: 85px;\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 89px;\"\u003e\n \u003cp\u003e0.40\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 665px;\"\u003e\n \u003cp\u003eAbbreviations. \u003cem\u003en:\u003c/em\u003e number of participants answered the question; E: women with endometriosis; C = controls; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = false discovery rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eThe endometriosis PGS was not associated with defaecation pattern regularity\u0026nbsp;(\u003cem\u003ep\u003c/em\u003e = 0.25), though it did associate with some of the gastrointestinal symptoms, i.e., abdominal pain (OR = 1.22, 95% CI = 1.01-1.47, \u003cem\u003ep\u003c/em\u003e = 0.04) and pain during food intake (OR = 2.60, 95% CI = 1.28-5.29, \u003cem\u003ep\u003c/em\u003e = 0.01). Furthermore, a doubling in genetic risk of endometriosis was associated with a 1.34 times greater risk of self-reported irritable bowel syndrome (95% CI = 1.06 \u0026ndash; 1.69, \u003cem\u003ep\u003c/em\u003e = 0.02).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eImpaired sleep quality in women with endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe found that women with endometriosis suffered more often from insomnia (OR = 1.38, 95% CI = 1.13 \u0026ndash; 1.67) and daytime fatigue (OR = 2.10, 95% CI = 1.53\u0026ndash; 2.88), but we found no difference in restless legs during sleep compared to controls (Table 6).\u0026nbsp;We did not find an increase in sleep problems related to the severity of endometriosis (\u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e \u0026gt; 0.1, Supplementary Table 2). Sleep characteristics, such as insomnia, daytime fatigue, and restless legs during sleep, were not associated with the endometriosis PGS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 6\u003c/strong\u003e. Sleep characteristics in women with endometriosis versus controls\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"555\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e\u0026nbsp;(E/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003eInsomnia, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e480/7,505\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e36.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e28.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003eDaytime fatigue, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e480/7,464\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e5.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 192px;\"\u003e\n \u003cp\u003eRestless legs during sleep, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e183/3,986\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e2.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 76px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 555px;\"\u003e\n \u003cp\u003eAbbreviations. \u003cem\u003en\u003c/em\u003e= number of participants answered the question; E= women with endometriosis; C = controls; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = false discovery rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eThe mental health of those with endometriosis is not affected\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe impact of health on an individual\u0026rsquo;s daily life was measured by the SF-12. We did not find any difference between women with endometriosis and their controls on the mental component of SF-12, though we found a lower score of the physical component (OR = 0.27, 95% CI = 0.19 \u0026ndash; 0.39) (Table 7). Women with severe endometriosis were not scoring lower on the SF-12 physical component than women with moderate endometriosis (FDR\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u0026gt; 0.1, Supplementary Table 2). No difference was found in perceived stress, but the major depression inventory (MDI) score was slightly higher in women with endometriosis (OR = 1.74, 95% CI = 1.10 \u0026ndash; 2.65), but they were not more often classified as patients with depression (i.e. MDI score \u0026gt; 20). The SF-12 physical component and MDI score were not associated with the endometriosis PGS.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 7.\u003c/strong\u003e Mental health in women with endometriosis versus controls\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 134px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eCharacteristics\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003en\u0026nbsp;\u003c/em\u003e\u003c/strong\u003e\u003cstrong\u003e(E/C)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eEndometriosis\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eControls\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u003cem\u003eP\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 277px;\"\u003e\n \u003cp\u003eSF-12 mental component, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e923/22,153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e52.3 (7.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e52.5 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 277px;\"\u003e\n \u003cp\u003eSF-12 physical component, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e923/22,153\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e53.5 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e55.0 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 277px;\"\u003e\n \u003cp\u003ePerceived stress scale, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e479/7,539\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e12.3 (5.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e12.4 (4.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003eDepression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 159px;\"\u003e\n \u003cp\u003eClassification, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e344/9,787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e14.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e11.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e1.00\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 119px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 159px;\"\u003e\n \u003cp\u003eMDI score, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 98px;\"\u003e\n \u003cp\u003e344/9,787\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 112px;\"\u003e\n \u003cp\u003e16.3 (4.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 110px;\"\u003e\n \u003cp\u003e15.8 (3.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"7\" valign=\"top\" style=\"width: 680px;\"\u003e\n \u003cp\u003eAbbreviations: \u003cem\u003en\u003c/em\u003e= number of participants answered the question; E=women with endometriosis; C= controls; SF-12= 12-item short form survey; MDI= major depression inventory; \u003cem\u003eP\u003c/em\u003e\u003csub\u003eFDR\u003c/sub\u003e = false discovery rate\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cstrong\u003eWomen with a high genetic risk of endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGiven that endometriosis often remains undiagnosed due to its non-specific symptoms, delays presenting to their doctors, and diagnostic challenges, we investigated whether women with a high genetic predisposition to endometriosis exhibit similar characteristics to those with a confirmed diagnosis. Therefore, we analysed individuals in the highest decile of PGS for endometriosis but without an endometriosis diagnosis, focusing on characteristics that significantly differed between these women and controls. Women with a high genetic risk for endometriosis, but without a diagnosis of endometriosis, more closely resembled controls than women with endometriosis diagnosis across most characteristics (Table 8). However, for two characteristics (postprandial pain and insomnia) women with a high genetic risk of endometriosis resembled women with endometriosis diagnosis, with both symptoms occurring more frequently than in age-matched controls. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 8.\u003c/strong\u003e Comparing characteristics of women with high PGS for endometriosis without endometriosis diagnosis, with women with endometriosis diagnosis, and with controls.\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" width=\"699\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 170px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP\u003c/strong\u003e-\u003cstrong\u003evalue\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTrait\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eE\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh PGS\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eC\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh PGS vs. E\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eHigh PGS vs. C\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eAge of onset induced menopause, mean (SD)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e40.0 (7.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e43.3 (7.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e43.0 (6.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.35\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eTried to conceive \u0026ge;6 months w/o success, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e45.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e23.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e21.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.07\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eDefaecation pattern regularity, irregular, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e18.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e12.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e12.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.67\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eAbdominal pain, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e29.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e22.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e17.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.004\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003ePostprandial pain, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e14.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e11.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e7.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eDefaecation pain, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e15.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e8.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e8.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.83\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eConstipation, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e20.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e15.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e12.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.03\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eIrritable bowel syndrome, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e20.0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e13.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e11.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eInsomnia, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e36.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e31.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e28.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eDaytime fatigue, %\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e10.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e6.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 293px;\"\u003e\n \u003cp\u003eSF12 \u0026ndash; physical component, mean (SD)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e53.5 (6.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e55.0 (5.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 76px;\"\u003e\n \u003cp\u003e54.9 (5.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 85px;\"\u003e\n \u003cp\u003e0.46\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"6\" style=\"width: 699px;\"\u003e\n \u003cp\u003eAbbreviations: E=women with endometriosis, PGS=Polygenic score, C=controls,\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"},{"header":"Discussion","content":"\u003cp\u003eEndometriosis is a heterogeneous, multifactorial, disease that presents many different symptoms and comorbidities \u003csup\u003e10\u003c/sup\u003e. In this study, we showed that women with endometriosis have compromised fertility, more gastrointestinal symptoms, and more sleep disturbances compared to age-matched women without endometriosis. We also showed that the PGS of endometriosis was higher in females with endometriosis than in those without endometriosis and, further, that this genetic burden was associated with gastrointestinal symptoms, potentially suggesting a shared genetic component of endometriosis and those comorbidities. However, in individuals without an endometriosis diagnosis, but with a high genetic burden for endometriosis (top decile PGS), we did not observe the same pattern of comorbidities as we saw in women with an endometriosis diagnosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePolygenic score predicting endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003ePreviously, two studies have investigated the polygenic score (PGS) of endometrioses \u003csup\u003e39,40\u003c/sup\u003e. Both studies used the 14 genome-wide significant loci that were found associated with endometriosis in, at that time, the largest GWAS of endometriosis available \u003csup\u003e41\u003c/sup\u003e. We calculated the PGS based on the most recent GWAS of endometriosis which increased the number of associated loci \u003csup\u003e21\u003c/sup\u003e. Moreover, in this study, we do not only use the significant SNPs but all available genetic variants, i.e., the whole genome, to capture as much of the genetic variability as possible. This resulted in a more precise (i.e., smaller p-value) but not higher prediction as our area under the receiver operating characteristic curve (AUC = 0.66) was similar to the one found by Kloeve-Mogensen \u003cem\u003eet al\u003c/em\u003e. (AUC = 0.64). Where Svensson \u003cem\u003eet al\u003c/em\u003e. did not find any difference between PGS and localization, Kloeve-Mogensen \u003cem\u003eet al\u003c/em\u003e. found a better prediction for ovarian endometriosis though not significantly different than the other localizations. In our study, we confirm the findings of Kloeve-Mogensen \u003cem\u003eet al\u003c/em\u003e, and with the increased sample size we do show a significant higher polygenic burden of endometriosis among women with severe endometriosis (stage III/IV) compared to those with moderate endometriosis (stage I/II). This finding supports the association between a higher genetic burden and greater disease severity \u003csup\u003e42,43\u003c/sup\u003e. Furthermore, we confirm this relationship by showing an elevated polygenic burden in individuals with endometriosis affecting multiple locations.\u003c/p\u003e\n\u003cp\u003eUsing the PGS, we investigated whether individuals with a high genetic burden (i.e., top decile PGS, capturing individuals with double risk of endometriosis) but without an endometriosis diagnosis were experiencing similar comorbidities as women diagnosed with endometriosis. While these individuals could provide insight into the consequences of underdiagnosis, in our study they did not show the same patterns of comorbidities as those with a confirmed diagnosis. One explanation is that endometriosis is a highly heterogeneous disease and women with undiagnosed endometriosis might have milder symptoms and did not seek medical attention, or were dismissed when presenting with these symptoms, leading to the perceived lack of a diagnosis and consequently fewer associated comorbidities. Additionally, factors beyond genetics\u0026mdash;including hormonal regulation, immune responses, and environmental influences\u0026mdash;likely contribute to disease expression and severity, further explaining differences in symptom burden. Another possibility is that the PGS does not fully capture the genetic complexity of endometriosis. While it reflects common genetic variants, endometriosis is a multifactorial disease likely influenced by rare variants, gene-gene, and gene-environment interactions, and epigenetic modifications that current PGS models may not adequately account for. However, we cannot rule out the possibility that these women may develop comorbidities later in life, given that participants in the DBDS cohort are relatively young (mean age of 44.6 years).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEndometriosis affects reproductive health\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eOne of the most well-established comorbidities of endometriosis is infertility; lesions can cause structural damage to the reproductive organs, alter hormonal signalling, and create an inflammatory environment that can impair fertility \u003csup\u003e44,45\u003c/sup\u003e. The elevated rate of women with endometriosis having challenges conceiving in our otherwise healthy cohort confirms the impact of endometriosis on fertility. It is important to note that among participants who responded \u0026apos;no\u0026apos; to \u0026ldquo;tried to conceive \u0026ge;6 months w/o success\u0026rdquo;, we were unable to distinguish between those who conceived within six months and those who had not attempted to conceive. Further, we found that women with endometriosis reported similar age at menarche compared to controls, while others have reported earlier age at menarche among women with endometriosis \u003csup\u003e46\u003c/sup\u003e. Furthermore, contrary to previous findings \u003csup\u003e47\u003c/sup\u003e, we did not find any evidence of shorter menstrual cycles in women with endometriosis, potentially due to the relatively large variation in the data. It has been hypothesized that an earlier, heavier, menstruation is a potential cause of endometriosis \u003csup\u003e48,49\u003c/sup\u003e; we did not find evidence supporting this hypothesis in our cohort. \u0026nbsp;However, contraceptive use was not considered in this analysis, potentially affecting results by altering menstrual characteristics such as cycle length and bleeding patterns, thereby obscuring natural associations with endometriosis. We observed that women with endometriosis experienced induced menopause three years earlier than women without endometriosis diagnosis, consistent with a recent large multi-cohort study reporting a 1.6-year earlier onset of surgical menopause \u003csup\u003e50\u003c/sup\u003e. In contrast, we did not observe a significant difference in the timing of natural menopause between women with and without endometriosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eWomen with endometriosis have more gastrointestinal symptoms\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAmong women with endometriosis, we observed a higher prevalence of irregular stool pattern and constipation. Moreover, women with endometriosis frequently reported gastrointestinal symptoms, including more abdominal pain, postprandial pain, and defaecation pain. This is in accordance with previous findings showing that women with endometriosis have more bowel symptoms than controls, also when no lesions where present on the bowel \u003csup\u003e51\u003c/sup\u003e. Furthermore, we found more constipation among those with stage III-IV endometriosis compared to those with stage I/II endometriosis; note that endometriosis located at the bowel is categorized under \u0026lsquo;ICD10: N80.8 - other endometriosis\u0026rsquo; and therefore classified as stage III-IV endometriosis. Further, we found an association between the genetic burden of endometriosis and pain-traits, i.e. abdominal pain and pain during food intake, indicating a genetic overlap between endometriosis and those comorbidities. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWe found a higher prevalence of self-reported irritable bowel syndrome among women with endometriosis, which is in line with a systematic review, that found a threefold increased risk of irritable bowel syndrome in women with endometriosis \u003csup\u003e52\u003c/sup\u003e. Irritable bowel syndrome and endometriosis have overlap in clinical symptoms, such as abdominal discomfort, pain, and cramping. Therefore, it is difficult to distinguish whether the symptoms are caused by endometriosis or irritable bowel syndrome, thus, misdiagnoses might occur as demonstrated by Nnoaham \u003cem\u003eet al.\u003c/em\u003e \u003csup\u003e53\u003c/sup\u003e. Furthermore, we found that the endometriosis PGS was significantly associated with self-reported irritable bowel syndrome, suggesting that individuals with a higher genetic predisposition for endometriosis are also more likely to report irritable bowel syndrome symptoms. While our data indicate an association, the underlying mechanisms remain to be clarified. One possible explanation is shared genetic architecture between the two conditions, which has been supported by prior studies demonstrating significant genetic correlations, such as the work by Yang \u003cem\u003eet al\u003c/em\u003e.\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003csup\u003e54\u003c/sup\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003eThough a study among women with celiac disease showed an increased risk of endometriosis \u003csup\u003e55\u003c/sup\u003e, we did not see any increased risk of self-reported celiac disease among women with endometriosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSleep and mental health affected by endometriosis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIt has previously been shown that insomnia and fatigue are more prevalent among women with endometriosis \u003csup\u003e56,57\u003c/sup\u003e, which was also confirmed in our study. We did not see an association between the genetic burden of endometriosis and insomnia or fatigue, indicating that the link between endometriosis and sleep is not due to shared genetic factors, but may be a consequence of increased levels of endometriosis-related pain, inflammation, and associated stress as previously demonstrated \u003csup\u003e58\u003c/sup\u003e. Furthermore, it is well-known that pain can affect sleep \u003csup\u003e59\u003c/sup\u003e. Whereas we did not find a genetic link between gastrointestinal pain and endometriosis, we did not investigate menstrual-related pain, and the latter may explain the link between endometriosis, pain, and sleep. A recently found association between restless legs syndrome and endometriosis was not confirmed in our study \u003csup\u003e\u0026nbsp;60\u003c/sup\u003e.\u003c/p\u003e\n\u003cp\u003eThe complexity of endometriosis and its comorbidities can have a major impact on mental health and overall quality of life, with higher levels of depressive and anxiety symptoms \u003csup\u003e61,62\u003c/sup\u003e. We identified a slightly elevated depression score in women with endometriosis compared to the control group, but an assessment using the SF-12 did not indicate a significant impact of endometriosis on mental health, as also demonstrated by Nnoaham \u003cem\u003eet al.\u003c/em\u003e.\u003csup\u003e\u0026nbsp;53\u0026nbsp;\u003c/sup\u003e Importantly, the absence of a robust association between endometriosis and mental health in our study could be attributed to the overall good health of our cohort (healthy donor effect), in contrast to a population-based cohort. Moreover, it has previously been shown that women with endometriosis without pelvic pain show no impact on psychological health compared to healthy women \u003csup\u003e63\u003c/sup\u003e.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStrengths and limitations\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DBDS comprises a mainly healthy cohort, as it is the responsibility of any blood bank to ensure that blood donors are healthy at the time of donating blood. \u0026nbsp;For example, individuals on long-term medical treatment are restricted from donating blood, although the use of contraception or paracetamol are not exclusion criteria. This practice introduces a selection bias, known as the healthy donor effect, which has also been shown in the DBDS cohort\u0026nbsp;\u003csup\u003e64\u003c/sup\u003e. As a result, there is an underrepresentation of physical health issues, together with elevated mental health levels, compared to the general population. Indeed, we observed a prevalence of endometriosis of 1.28%, which is significantly lower than the Danish prevalence of endometriosis diagnosed at hospital of 1.63% in 2017\u0026nbsp;\u003csup\u003e65\u003c/sup\u003e. This suggests that women with endometriosis who are on long-term medications for the severity of their symptoms, are not blood donors.\u0026nbsp;Importantly, many of our findings are consistent with previous studies, showing that endometriosis does not only affect women experiencing severe symptoms, and reminds us that the extent of endometriotic lesions does not necessarily correlate with symptoms, treatment response, or prognosis \u003csup\u003e66\u003c/sup\u003e. We confirm this in our study: only constipation was more prevalent among women with stage III/IV endometriosis than among women with stage I/II endometriosis. Furthermore, the actual estimated prevalence of endometriosis in the general population is ten percent among women in reproductive age\u0026nbsp;\u003csup\u003e10\u003c/sup\u003e. This discrepancy prompts consideration of potential underdiagnosis, a well-known challenge in endometriosis.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn this study, results are based on self-reported questionnaires, where participants\u0026apos; responses may be subjective and influenced by their personal perspectives, potentially affecting the precision of the data collected. However, high genetic correlations have been found between self-reported diseases and clinically diagnosed diseases \u003csup\u003e67\u003c/sup\u003e. Furthermore, the responses are limited by potential recall bias, influencing the accuracy of participants\u0026apos; recollection of past events or experiences. In the case of self-reported diseases, and in case of diseases with overlapping symptoms such as endometriosis and irritable bowel syndrome, we acknowledge the potential for misclassification bias. The potential for confounding variables, sampling bias, and the challenge of establishing a clear temporal relationship further contribute to the complexity of interpreting our results.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThis study is a retrospective study, and we defined the participant as \u0026lsquo;a case\u0026rsquo; when the questionnaire was filled in after a diagnosis of endometriosis. As there is a substantial delay \u003csup\u003e14\u0026ndash;16\u003c/sup\u003e in diagnosing endometriosis, this may affect our results in different ways. Firstly, the delayed diagnosis may skew the representation of endometriosis severity, potentially underrepresenting milder cases where individuals have adapted to the disease over time, which affects the generalizability of our results across the entire spectrum of endometriosis severity. Secondly, delayed diagnosis affects the temporal aspect of comorbidity associations. Prolonged exposure to endometriosis without early intervention may contribute to the development of certain comorbidities \u003csup\u003e18,53,68\u003c/sup\u003e. Therefore, our findings not only highlight the inherent association between endometriosis and comorbidities but also underscore the impact of delayed diagnosis on these observed relationships. Lastly, both the delay between symptom onset and diagnosis, and the subsequent delay in initiating treatment, may act as confounding factors by influencing the severity or progression of comorbidities. For instance, longer periods without appropriate management may allow comorbid conditions to develop or worsen, thereby exaggerating their association with endometriosis in our data. Variations in treatment regimens and their effectiveness over the extended life course of the disease may influence the prevalence and severity of associated comorbidities in the endometriosis group, necessitating a cautious interpretation of these relationships. Unfortunately, our sample size did not provide enough statistical power to investigate the effect of treatment after receiving a diagnosis.\u0026nbsp;\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eEndometriosis is a heterogeneous, multifactorial disease characterized by diverse symptoms and comorbidities. In this study, we demonstrated that women with endometriosis experience compromised fertility, increased gastrointestinal symptoms, and more frequent sleep disturbances compared to age-matched female controls. We also found that the PGS for endometriosis was higher in women with a diagnosis than in those without, and that this genetic burden was associated with gastrointestinal symptoms, suggesting a potential shared genetic basis. However, women without a diagnosis but with a high genetic predisposition for endometriosis did not exhibit the same broad pattern of comorbidities as seen in diagnosed cases. Our study contributes valuable insights, as well as confirmation of results from previous studies in different cohorts, into the complex interplay between endometriosis and comorbidities, underscoring the need for studying and treating endometriosis as the heterogenous disease that it is.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eDBDS: Danish Blood Donor Study\u003c/p\u003e\n\u003cp\u003ePGS: Polygenic score\u003c/p\u003e\n\u003cp\u003eOR: Odds ratio\u003c/p\u003e\n\u003cp\u003eGWAS: genome-wide association studies\u003c/p\u003e\n\u003cp\u003eSF12: Short Form Health Survey 12\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDNPR: Danish National Patient Registry\u003c/p\u003e\n\u003cp\u003ePCs: principal components\u003c/p\u003e\n\u003cp\u003eLD: linkage disequilibrium\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePCS: physical component summary score\u003c/p\u003e\n\u003cp\u003eMCS: mental component summary score\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePSS: Cohen\u0026rsquo;s Perceived Stress Scale\u003c/p\u003e\n\u003cp\u003eMDI: Major Depression Inventory\u003c/p\u003e\n\u003cp\u003eAUC: area under the curve\u003c/p\u003e\n\u003cp\u003eFDR: False Discovery Rate\u003c/p\u003e\n\u003cp\u003eSD: standard deviation\u0026nbsp;\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical statements.\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe DBDS has the necessary permissions and approval from the Danish Data Protection Agency (2007-58-0015) and the Scientific Ethical Committee system (M-20090237). All participants provided informed oral and written consent to participate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData cannot be made publicly available, but the DBDS is open for collaboration. Enquiries regarding collaboration can be addressed to the DBDS steering committee. Potential collaborators are encouraged to find additional information and contact details on our homepage www.dbds.dk.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCLH received research support from Novo Nordisk Foundataion (grant no. NNF22OC0074080) and lecture fees from BMS, Janssen, Tillotts, Servier, and Merck. All other authors do not report any conflicts of interest.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by a grant from the Novo Nordisk Foundation to MN (grant number NNF21OC0071050). This article is part of the project Finding Endometriosis using Machine Learning (FEMaLe/101017562), which has received funding from the European Union\u0026apos;s Horizon 2020 research and innovation program. \u0026nbsp;The Danish Blood Donor Study (DBDS) is funded by an annual grant from Bio- and Genome Bank Denmark. The initiation of DBDS was supported by the Danish Administrative Regions (02/2611) and the Danish Council for Independent Research (09\u0026ndash;069412). Additionally, the DBDS is funded by the Novo Nordisk Foundation (NNF23OC0082015, NNF17OC0027864, and NNF17OC0027594). \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eLK performed the formal analysis, developed the methodology, created the visualizations, and was the lead author of the original draft. DR, LH, KEH, UBK, JLB, and HSN contributed to writing, review, and editing of the manuscript. JTB, MTB, NB, CE, BAJ, BDK, CM, SM, SRO, OBP, ES, HU, AKG, CLH, VS, and KS provided resources and contributed to data acquisition. KB and PDR contributed to the methodology and to writing, review, and editing of the manuscript. MN was responsible for the conceptualisation of the study, acquisition of funding, development of methodology, and supervision of the writing and review process. All authors have read, reviewed, and approved the final version of the manuscript. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the staff of the Danish blood banks and the Danish blood donors for their participation, enabling us to carry out this research.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eEisenberg VH, Decter DH, Chodick G, et al. Burden of Endometriosis: Infertility, Comorbidities, and Healthcare Resource Utilization. \u003cem\u003eJournal of Clinical Medicine 2022, Vol 11, Page 1133\u003c/em\u003e 2022; 11: 1133.\u003c/li\u003e\n\u003cli\u003eSoliman AM, Surrey E, Bonafede M, et al. Real-World Evaluation of Direct and Indirect Economic Burden Among Endometriosis Patients in the United States. \u003cem\u003eAdv Ther\u003c/em\u003e 2018; 35: 408.\u003c/li\u003e\n\u003cli\u003eShafrir AL, Farland L V., Shah DK, et al. 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ARTICLE Assessing Digital Phenotyping to Enhance Genetic Studies of Human Diseases. \u003cem\u003eThe American Journal of Human Genetics\u003c/em\u003e 2020; 106: 611\u0026ndash;622.\u003c/li\u003e\n\u003cli\u003eTaylor HS, Kotlyar AM, Flores VA. Endometriosis is a chronic systemic disease: clinical challenges and novel innovations. \u003cem\u003eThe Lancet\u003c/em\u003e 2021; 397: 839\u0026ndash;852.\u003c/li\u003e\n\u003c/ol\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-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"endometriosis, comorbidities, polygenic score, genetic burden","lastPublishedDoi":"10.21203/rs.3.rs-6620337/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6620337/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Endometriosis is a complex condition with a wide range of comorbidities. It is widely underdiagnosed, with a diagnostic delay of 4 to 10 years, potentially leading to worsened disease progression and a higher burden of comorbidities affecting quality of life. Understanding the link between endometriosis and its comorbidities is essential for improving early detection of the disease.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: We analysed data from 953 women with a clinical diagnosis of endometriosis and 23,652 age-matched female controls enrolled in the Danish Blood Donor Study. Participants completed one to four questionnaires covering a wide range of potential comorbidities; genetic data were available for a subset of participants. First, we compared the potential comorbidities between women with endometriosis and controls. Next, we investigated whether a polygenic score (PGS) for endometriosis was associated with those comorbidities. Lastly, we investigated whether women with a high genetic burden of endometriosis (highest PGS decile) experienced similar comorbidities to those diagnosed with endometriosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: Women with endometriosis experienced challenges in conception, gastrointestinal symptoms, disturbed sleep patterns, and slightly lower mental health scores, compared to age-matched controls. The endometriosis PGS showed to be a predictor for endometriosis (OR per unit PGS = 1.43, 95% CI = 1.32 – 1.55). Gastrointestinal symptoms were also associated with the endometriosis PGS, indicating shared genetic pathways. Women without a diagnosis of endometriosis but with a high genetic burden of endometriosis did not suffer from the same wide range of comorbidities as women diagnosed with endometriosis.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Our findings highlight the complex genetic and clinical relationships between endometriosis and its comorbidities emphasizing the need for future research investigating potential endometriosis subtypes.\u003c/p\u003e","manuscriptTitle":"The burden of endometriosis on quality of life in Danish blood donors","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-06-05 10:24:12","doi":"10.21203/rs.3.rs-6620337/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-23T14:50:04+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-20T14:13:13+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-06-16T09:51:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"23443702486170813690803643493535431087","date":"2025-06-14T13:53:55+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"106298175317063426009381181128347634569","date":"2025-06-12T13:32:38+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-16T11:48:14+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-09T08:59:45+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-09T08:38:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Medicine","date":"2025-05-08T11:38:02+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-medicine","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bmed","sideBox":"Learn more about [BMC Medicine](http://bmcmedicine.biomedcentral.com/)","snPcode":"12916","submissionUrl":"https://submission.nature.com/new-submission/12916/3","title":"BMC Medicine","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"1b3ae414-4075-4f74-a023-928cce7baab9","owner":[],"postedDate":"June 5th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:11:00+00:00","versionOfRecord":{"articleIdentity":"rs-6620337","link":"https://doi.org/10.1186/s12916-025-04398-z","journal":{"identity":"bmc-medicine","isVorOnly":false,"title":"BMC Medicine"},"publishedOn":"2025-10-14 15:57:26","publishedOnDateReadable":"October 14th, 2025"},"versionCreatedAt":"2025-06-05 10:24:12","video":"","vorDoi":"10.1186/s12916-025-04398-z","vorDoiUrl":"https://doi.org/10.1186/s12916-025-04398-z","workflowStages":[]},"version":"v1","identity":"rs-6620337","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6620337","identity":"rs-6620337","version":["v1"]},"buildId":"B-jG_2CBjPDmsCi4Wdhf-","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}