Endometriosis is a chronic inflammatory disease associated with pelvic pain, infertility, and delayed diagnosis. Growing evidence suggests that altered DNA methylation contributes to disease development and could serve as a biomarker for disease. We developed a leakage-safe machine learning pipeline to classify endometriosis case-control status and menstrual cycle phase using genome-wide DNA methylation data from eutopic endometrial tissue. The dataset consisted of 984 samples profiled using the Illumina Infinium MethylationEPIC array, with measurements across approximately 759,000 CpG sites. Technical variation was corrected using SmartSVA batch correction. Ridge logistic regression models were trained using stratified 80/20 train-test splits, with regularization strength selected via stratified cross-validation. Feature selection approaches included ridge coefficient ranking, per-CpG t-tests, and univariate logistic regression with FDR correction. Model validity was evaluated using label-shuffling analyses. Menstrual cycle phase classification showed strong performance (mean cross-validation AUROC: 0.971, held-out test AUROC: 0.989), reflecting genome-wide hormonally driven methylation. Ridge regression produced lower but meaningful performance for endometriosis classification (mean cross-validation AUROC: 0.854, held-out test AUROC: 0.875). Ridge coefficient-based feature selection identified compact predictive CpG sets, supporting the hypothesis that endometriosis-associated methylation signal is distributed across many loci rather than a few highly predictive CpGs. Pathway enrichment analyses identified substantial enrichment for menstrual cycle phase but limited enrichment for disease status following FDR correction, consistent with a diffuse endometriosis-associated signal. These findings demonstrate that ridge regression can detect methylation patterns associated with both endometriosis and menstrual cycle phase, highlighting the importance of accounting for cycle-related epigenetic variation in endometrial DNA methylation studies.

BACKGROUND: Conditioned pain modulation (CPM) is considered a human proxy for descending inhibitory pain pathways. However, there is wide variation in the CPM response described in the literature and ongoing debate about its utility. METHODS: Here we explored CPM in women with (n = 59) and without (n = 26) chronic pelvic pain (CPP), aiming to determine the magnitude of effect and factors influencing variability in the CPM response. RESULTS: Using a pressure pain threshold test stimulus and ischaemic pressure cuff conditioning stimulus (CS), we found no significant difference in the mean CPM effect between CPP and control participants. Using a robust statistical method (+/-2 standard error of measurement) to further investigate CPM, there was no significant difference in the proportion exhibiting inhibition between controls and CPP participants (X2 = 0.003, p = 0.96). Notably, only 23.1% of our healthy controls demonstrated a "true" CPM effect (n = 4 inhibitory, n = 2 facilitatory). Despite a rich data set, we were unable to identify any single questionnaire, clinical or psychophysical covariate correlating with the CPM effect. CONCLUSIONS: Despite using one of the recommended CPM paradigms we were only able to demonstrate "true" CPM in 23.1% of control participants. Thus, the absence of differences between women with and without chronic pelvic pain must be interpreted with caution. Future studies using different CPM paradigms or larger sample sizes may find different results. Although CPM in chronic pain populations is of major theoretical mechanistic interest, the lack of an established assessment standard led us to question its added value in current clinical research.

STUDY QUESTION:Is there an increased risk of immunological diseases among endometriosis patients, and does a shared genetic basis contribute to this risk? SUMMARY ANSWER:Endometriosis patients show a significantly increased risk of autoimmune, autoinflammatory, and mixed-pattern diseases, including rheumatoid arthritis, multiple sclerosis, coeliac disease, osteoarthritis, and psoriasis, with genetic correlations between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis, and a potential causal link to rheumatoid arthritis. WHAT IS KNOWN ALREADY:The epidemiological evidence for an increased risk of immunological diseases among women with endometriosis is limited in scope and has varied in robustness due to the opportunity for biases. The presence of a biological basis for increased comorbidity across immunological conditions has not been investigated. Here we investigate the phenotypic and genetic association between endometriosis and 31 immune conditions in the UK Biobank. STUDY DESIGN, SIZE, DURATION:Phenotypic analyses between endometriosis and immune conditions (17 classical autoimmune, 10 autoinflammatory, and 4 mixed-pattern diseases) were conducted using two approaches (8223 endometriosis, 64 620 immunological disease cases): (i) retrospective cohort study design to incorporate temporality between diagnoses and (ii) cross-sectional analysis for simple association. Genome-wide association studies (GWAS) and meta-analyses for those immune conditions that showed phenotypic association with endometriosis (1493-77 052 cases) were conducted. PARTICIPANTS/MATERIALS, SETTING, METHODS:Comprehensive phenotypic association analyses were conducted in females in the UK Biobank. GWAS for immunological conditions were conducted in females-only and sex-combined study populations in UK Biobank and meta-analysed with existing largest available GWAS results. Genetic correlation and Mendelian randomization (MR) analyses were conducted to investigate potential causal relationships. Those immune conditions with significant genetic correlation with endometriosis were included in multi-trait analysis of GWAS to boost discovery of novel and shared genetic variants. These shared variants were functionally annotated to identify affected genes utilizing expression quantitative trait loci (eQTL) data from GTEx and eQTLGen databases. Biological pathway enrichment analysis was conducted to identify shared underlying biological pathways. MAIN RESULTS AND THE ROLE OF CHANCE:In both retrospective cohort and cross-sectional analyses, endometriosis patients were at significantly increased (30-80%) risk of classical autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis), and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic correlation (rg) = 0.28, P = 3.25 × 10-15), rheumatoid arthritis (rg = 0.27, P = 1.5 × 10-5) and multiple sclerosis (rg = 0.09, P = 4.00 × 10-3) were significantly genetically correlated with endometriosis. MR analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR = 1.16, 95% CI = 1.02-1.33). eQTL analyses highlighted genes affected by shared risk variants, enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis (BMPR2/2q33.1, BSN/3p21.31, MLLT10/10p12.31) and one with rheumatoid arthritis (XKR6/8p23.1). LIMITATIONS, REASONS FOR CAUTION:We conducted the first female-specific GWAS analyses for immune conditions. Given the novelty of these analyses, the sample sizes from which results were derived were limited compared to sex-combined GWAS meta-analyses, which limited the power to use female-specific summary statistics to uncover the shared genetic basis with endometriosis in follow-up analyses. Secondly, the 39 genome-wide significant endometriosis-associated variants used as instrumental variables in the MR analysis explained approximately 5% of disease variation, which may account for the nominal or non-significant MR results. WIDER IMPLICATIONS OF THE FINDINGS:Endometriosis patients have a moderately increased risk for osteoarthritis, rheumatoid arthritis, and to a lesser extent, multiple sclerosis, due to underlying shared biological mechanisms. Clinical implications primarily involve the need for increased awareness and vigilance. The shared genetic basis opens up opportunities for developing new treatments or repurposing therapies across these conditions. STUDY FUNDING/COMPETING INTEREST(S):We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from the Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by the National Natural Science Foundation of China (grant 32170663). N.R., S.A.M., and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). K.T.Z. and C.M.B. reported grants in 3 years prior, outside the submitted work, from Bayer AG, AbbVie Inc., Volition Rx, MDNA Life Sciences, PrecisionLife Ltd., and Roche Diagnostics Inc. S.A.M. reports grants in the 3 years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio, outside this submitted work. The other authors have no conflicts of interest to declare. TRIAL REGISTRATION NUMBER:N/A.

Objectives:To translate and cross-culturally adapt the standard version of the WERF EPHect EPQ into Brazilian Portuguese and migrate it to an electronic version using REDCap. Methods:The study included 120 women aged 18-50 years, with half completing the paper version and half the electronic version. The sample comprised 80 individuals with chronic pelvic pain (CPP), including 60 with endometriosis, recruited from a tertiary referral centre, and 40 women from a primary healthcare unit with no diagnosis of CPP or endometriosis. Illiterate or cognitively impaired individuals were excluded. The electronic migration was implemented in REDCap. Results:The Brazilian Portuguese EPQ-S demonstrated linguistic accuracy and cultural equivalence to the original English version. The paper version consisted of 35 pages, and 86.7% of respondents commented on its length. Despite this, it was well-received, although minor difficulties were observed among participants with lower education levels. The electronic version provided a more accessible experience, with a significantly shorter completion time (52.1 ± 13.2 minutes) compared to the paper version (70.9 ± 21.4 minutes). Both formats exhibited similar rates of missing data for questions related to symptoms and contraceptive use. Conclusion:This study successfully translated, adapted, and migrated the WERF EPHect EPQ-S into Brazilian Portuguese using REDCap. The findings underscore the linguistic and cultural challenges of such adaptations and highlight the electronic version's advantages in accessibility, efficiency, and participant satisfaction. This research supports the development of cross-cultural assessment tools for endometriosis research and healthcare delivery.

Graphical abstract Abstract Immunological dysregulation plays a fundamental role in the inflammatory aspects of endometriosis. Circulating blood leukocytes, one of the most abundant immune cell populations in the human body, have been shown diagnostic significance in some diseases. Nevertheless, the association between peripheral blood leukocyte counts and endometriosis remains unexplored to date. We analyzed two targeted study cohorts: a tertiary center cohort (Endometriosis at Oxford University (ENDOX) Study: 325 cases/177 controls) and a large-scale population study (UK Biobank (UKBB): 1537 cases/6331 controls). In both datasets, peripheral venous blood sample results were retrieved, and counts of leukocyte subpopulations, including neutrophils, lymphocytes, monocytes, eosinophils, and basophils, were analyzed. Logistic regression models were used to investigate the association of leukocyte subtype alterations with endometriosis status, adjusting for confounding factors. We demonstrate that a higher blood basophil level is associated with increased odds of endometriosis. This association was first discovered in the ENDOX cohort (basophils >0.04 × 109/L: OR 1.65 (95% CI: 1.06–2.57), Ptrend = 0.025) and replicated in the UKBB dataset (basophils >0.04 × 109/L: OR 1.26 (95% CI: 1.09–1.45), Ptrend = 0.001). Notably, women with basophil counts in the upper tercile had significantly increased odds of having stage III/IV endometriosis (ENDOX study: OR = 2.30, 95% CI (1.25–4.22), Ptrend = 0.007; UKBB study (OR = 1.40, 95% CI (1.07–1.85), Ptrend = 0.015). None of the other leukocyte subtypes showed an association. Our findings suggest an association between inflammatory responses and the pathogenesis of endometriosis; future studies are warranted to investigate whether the association is causal. Lay summary Endometriosis is a long-term disease affecting approximately 10% of women during their fertile age. It happens when the tissue similar to the lining of the womb grows in other parts of the body, commonly causing pelvic pain and subfertility. Most diagnostic tests for endometriosis are neither accurate nor reliable, leading to a long wait before a correct diagnosis. Looking for changes in blood cell counts could guide doctors for further testing to confirm diagnosis. Our study shows that a higher number of basophils, a specialized type of white cells, commonly measured in a simple blood test, are positively linked with a higher likelihood of endometriosis. The link becomes stronger in severe endometriosis cases. Although we are showing a robust link, whether this can be used to find endometriosis sooner needs to be tested in future studies.

BACKGROUND:Endometriosis is an estrogen-dependent, chronic inflammatory disease that affects 10% of women during the reproductive ages. Despite the estimated 50% heritability for the condition, only 26% was associated with common genetic variants. Thus, necessity of identifying rare variants for the missing heritability is implicated in the literature. Therefore, our study aimed to identify novel rare genetic variants involved in the pathogenesis of endometriosis utilizing a family of multiple affected members.METHODS:A family composed of four affected women along with their two unaffected mothers were recruited at a single gynecology and infertility clinic specialized in endometriosis. All patients presented with endometriomas, which was visualized by transvaginal ultrasonography. Two affected individuals had received laparoscopic endometrioma excision and therefore were diagnosed with recurrent disease. One mother had a history of endometrial serous adenocarcinoma (ESC) for which she underwent hysterectomy with bilateral oophorectomy. Three endometriosis cases were whole exome sequenced on Illumina NextSeq 550 platform with an average of 90% coverage. Candidate genes were confirmed by Sanger sequencing and followed-up with family segregation.RESULTS:Novel rare variants were identified in TNFRSF1B (NM_001066.3: c.1072G>A, p.(Ala358Thr)) and GEN1 (NM_001130009.3: c.1574C>T, p.(Ser525Leu)) as possible genetic causes of endometriosis. A third novel rare variant was identified in CRABP1 (NM_004378.3:c.54G>C, p.(Glu18Asp)) only on the mother with ESC history and her daughters.CONCLUSION:Novel candidate genetic variants that might contribute to endometriosis were suggested that need replication through independent cohorts or validation by functional studies. The family has also received genetic counseling and that the affected daughters are on clinical follow-up, accordingly.

Endometriosis is an inflammatory condition affecting approximately 10% of the female-born population. Despite its prevalence, the lack of noninvasive biomarkers has contributed to an established global diagnostic delay. The intricate pathophysiology of this enigmatic disease may leave signatures in the blood, which, when detected, can be used as noninvasive biomarkers. This review provides an update on how investigators are utilizing the established disease pathways and innovative methodologies, including genome-wide association studies, next-generation sequencing, and machine learning, to unravel the clues left in the blood to develop blood biomarkers. Many blood biomarkers show promise in the discovery phase, but because of a lack of standardized and robust methodologies, they rarely progress to the development stages. However, we are now seeing biomarkers being validated with high diagnostic accuracy and improvements in standardization protocols, providing promise for the future of endometriosis blood biomarkers.

Chronic pelvic pain (CPP) in women with no obvious pelvic pathology has few evidence-based treatment options. Our recent multicenter randomized controlled trial (GaPP2) in women with CPP and no obvious pelvic pathology showed that gabapentin did not relieve pain overall and was associated with more side effects than placebo. We conducted an exploratory genome-wide association study using eligible GaPP2 participants aiming to identify genetic variants associated with gabapentin response. One genome-wide significant association with gabapentin analgesic response was identified, rs4442490, an intron variant located in Neuregulin 3 (NRG3) (p = 2·11×10-8; OR = 18·82 (95% CI 4·86-72·83). Analysis of a large sample of UK Biobank participants demonstrated phenome-wide significant brain imaging features of rs4442490, particularly implicating the orbitofrontal cortex. NRG3 is expressed predominantly in central nervous system tissues and plays a critical role in nervous system development, maintenance, and repair, suggesting a neurobiologically plausible role in gabapentin efficacy and potential for personalized analgesic treatment.

BACKGROUND:There are limited data on endometriosis from the Eastern Mediterranean region. This study for the first time estimates the prevalence and impact of endometriosis on women in Northern Cyprus, an under-represented region in Europe. METHODS:Cyprus Women's Health Research Initiative, a cross-sectional study recruited 7646 women aged 18-55 in Northern Cyprus between January 2018 and February 2020. Cases were identified using self-reported and ultrasound data and two control groups were defined, with (n = 2922) and without (n = 4314) pain. Standardized tools, including the 11-point Numerical Rating Scale and the Short Form 36 Health Survey version 2, were used to assess pain and quality of life, respectively. RESULTS:Prevalence and median diagnostic delay of endometriosis were 5.4% [95% confidence interval (CI): 4.9-5.9%, n = 410] and 7 (interquartile range 15.5) years. Endometriosis cases experienced a higher prevalence of bladder pain compared with asymptomatic pain controls (6.3% vs. 1.0%, P < 0.001) and irritable bowel syndrome relating to pelvic pain compared with symptomatic (4.6% vs. 2.6%, P = 0.027) and asymptomatic (0.3%, P < 0.001) controls. The odds of endometriosis cases reporting an anxiety diagnosis was 1.56 (95% CI: 1.03-2.38) higher than the symptomatic and 1.95 (95% CI: 1.30-2.92) times higher than the asymptomatic controls. The physical component score of the health-related quality-of-life instrument suggested a significant difference between the endometriosis cases and the symptomatic controls (46.8 vs. 48.5, P = 0.034). Average annual economic cost of endometriosis cases was Int$9864 (95% CI: $8811-$10 917) including healthcare, costs relating to absence and loss of productivity at work. CONCLUSION:Prevalence was lower than the global 10% estimate, and substantial proportion of women without endometriosis reported moderate/severe pelvic pain hinting at many undiagnosed cases within this population. Coupled with lower quality of life, significant economic burden and underutilized pain management options, the study highlights multiple opportunities to improve care for endometriosis patients and women with pelvic pain.

The evidence for a greater prevalence of immunological diseases among endometriosis patients has varied in robustness and been subject to selection bias. We investigated the phenotypic and genetic association between endometriosis and 31 immunological diseases in the UK Biobank (8,223 endometriosis, 64,620 immunological disease cases). In cross-sectional and retrospective cohort analyses, endometriosis patients were at significantly increased (30-80%) risk of classical-autoimmune (rheumatoid arthritis, multiple sclerosis, coeliac disease), autoinflammatory (osteoarthritis) and mixed-pattern (psoriasis) diseases. Osteoarthritis (genetic-correlation (rg)=0.28, P=3.25x10-15), rheumatoid arthritis (rg=0.27, P=1.54x10-5) and multiple sclerosis (rg=0.09, P=4.00x10-3) were significantly genetically correlated with endometriosis. Mendelian randomisation analysis suggested a causal association between endometriosis and rheumatoid arthritis (OR=1.16, 95%CI=1.02-1.33). Expression QTL analyses highlighted effector genes enriched for seven pathways across all four conditions, with three genetic loci shared between endometriosis and osteoarthritis and one with rheumatoid arthritis. Although the increased risk of immunological diseases among endometriosis patients is modest, their shared genetic basis opens-up opportunities for new treatments. ### Competing Interest Statement K.T.Z. and C.M.B. reported grants in three years prior, outside the submitted work, from Bayer AG, AbbVie Inc, Volition Rx, MDNA Life Sciences, PrecisionLife Ltd, Roche Diagnostics Inc. S.A.M. reports grants in the three years prior, outside this submitted work, from AbbVie Inc. N.R. is a consultant for Endogene.bio. ### Funding Statement We thank all the UK Biobank and 23andMe participants. Part of this research was conducted using the UK Biobank Resource under Application Number 9637. N.R. was supported by a grant from Wellbeing of Women UK (RG2031) and the EU Horizon 2020 funded project FEMaLe (101017562). A.P.M. was supported in part by Versus Arthritis (grant 21754). H.F. was supported by National Natural Science Foundation of China (grant 32170663). N.R., S.A.M and K.T.Z. were supported in part by a grant from CDMRP DoD PRMRP (W81XWH-20-PRMRP-IIRA). S.A.M. and K.T.Z. gratefully acknowledge funding provided by the Nezhat Family Foundation on behalf of Worldwide EndoMarch to their research programmes. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Data from UK biobank was utilised (Application Number 9637) and publicly available GWAS summary statistics for immunological conditions. The UK Biobank was approved by the North West Multi-Centre Research Ethics Committee (MREC). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The GWAS meta-analyses for immunological conditions made use of data from the UK Biobank (Application Number 9637) and publicly available GWAS summary statistics for immunological conditions. GWAS data for endometriosis was based on the latest analyses of International Endogene Consortium: summary statistics excluding 23andMe data is available from EBI GWAS Catalog Study Accession GCST90205183; endometriosis GWAS summary statistics from 23andMe, Inc. were made available under a data use agreement that protects participant privacy. Please contact dataset-request@23andme. com or visit research.23andMe.com/collaborate for more information and to apply to access the data.

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Chronic pelvic pain (CPP) is a common condition affecting up to 26.6% of women, with many suffering for several years before diagnosis and/or treatment. Its clinical presentation is varied and there are frequently comorbid conditions both within and outside the pelvis. We aim to explore whether specific subgroups of women with CPP report different clinical symptoms and differing impact of pain on their quality of life (QoL).The study is part of the Translational Research in Pelvic Pain (TRiPP) project which is a cross-sectional observational cohort study. The study includes 769 female participants of reproductive age who completed an extensive set of questions derived from standardised WERF EPHect questionnaires. Within this population we defined a control group (reporting no pelvic pain, no bladder pain syndrome, and no endometriosis diagnosis, N = 230) and four pain groups: endometriosis-associated pain (EAP, N = 237), interstitial cystitis/bladder pain syndrome (BPS, N = 72), comorbid endometriosis-associated pain and BPS (EABP, N = 120), and pelvic pain only (PP, N = 127).Clinical profiles of women with CPP (13-50 years old) show variability of clinical symptoms. The EAP and EABP groups scored higher than the PP group (p < 0.001) on the pain intensity scales for non-cyclical pelvic pain and higher than both the BPS and PP groups (p < 0.001) on the dysmenorrhoea scale. The EABP group also had significantly higher scores for dyspareunia (p < 0.001), even though more than 50% of sexually active participants in each pain group reported interrupting and/or avoiding sexual intercourse due to pain in the last 12 months. Scores for the QoL questionnaire (SF-36) reveal that CPP patients had significantly lower QoL across all SF-36 subscales (p < 0.001). Significant effects were also observed between the pain groups for pain interference with their work (p < 0.001) and daily lives (p < 0.001), with the EABP suffering more compared to the EAP and PP groups (p < 0.001).Our results demonstrate the negative impact that chronic pain has on CPP patients' QoL and reveal an increased negative impact of pain on the comorbid EABP group. Furthermore, it demonstrates the importance of dyspareunia in women with CPP. Overall, our results demonstrate the need for further exploration of interventions targeting QoL more broadly and suggest that novel approaches to classifying women with CPP are needed.

INTRODUCTION:Caesarean section (C-section) is a life-saving procedure when medically indicated but unmet need and overuse can add to avoidable morbidity and mortality. It is not clear whether C-section has a negative impact on breastfeeding and there is limited data available on rates of C-section or breastfeeding from Northern Cyprus, an emerging region in Europe. This study aimed to investigate prevalence, trends and associations of C-section and breastfeeding in this population.METHODS:Using self-reported data from the representative Cyprus Women's Health Research (COHERE) Initiative, we used 2,836 first pregnancies to describe trends in C-section and breastfeeding between 1981 and 2017. Using modified Poisson regression, we examined the relationship between year of pregnancy and C-section and breastfeeding, as well as the association between C-section and breastfeeding prevalence and duration.RESULTS:C-section prevalence in first pregnancies increased from 11.1% in 1981 to 72.5% in 2017 with a relative risk of 2.60 (95%CI; 2.14-2.15) of babies being delivered by C-section after 2005 compared to before 1995, after full adjustment for demographic and maternal medical and pregnancy related factors. Prevalence of ever breastfeeding remained steady throughout the years at 88.7% and there was no significant association between breastfeeding initiation and the year of pregnancy, or demographic and maternal medical and pregnancy related variables. After full adjustment, women who gave birth after 2005 were 1.24 (95%CI; 1.06-1.45) times more likely to breastfeed for >12 weeks compared to women who gave birth before 1995. There was no association between C-section and breastfeeding prevalence or length.CONCLUSION:Prevalence of C-section in this population is much higher than WHO recommendations. Public awareness campaigns surrounding choice during pregnancy and change in legal framework to allow for midwife-led continuity models of birthing care should be implemented. Further research is required to understand the reasons and drivers behind this high rate.

Endometriosis is a common condition associated with debilitating pelvic pain and infertility. A genome-wide association study meta-analysis, including 60,674 cases and 701,926 controls of European and East Asian descent, identified 42 genome-wide significant loci comprising 49 distinct association signals. Effect sizes were largest for stage 3/4 disease, driven by ovarian endometriosis. Identified signals explained up to 5.01% of disease variance and regulated expression or methylation of genes in endometrium and blood, many of which were associated with pain perception/maintenance (SRP14/BMF, GDAP1, MLLT10, BSN and NGF). We observed significant genetic correlations between endometriosis and 11 pain conditions, including migraine, back and multisite chronic pain (MCP), as well as inflammatory conditions, including asthma and osteoarthritis. Multitrait genetic analyses identified substantial sharing of variants associated with endometriosis and MCP/migraine. Targeted investigations of genetically regulated mechanisms shared between endometriosis and other pain conditions are needed to aid the development of new treatments and facilitate early symptomatic intervention. Meta-analyses of genome-wide association studies for endometriosis identify 49 distinct association signals. Fine-mapping of causal variants explores functional effects across various tissues. Genetic correlations between endometriosis and other pain conditions are also highlighted.

Endometriosis is a leading cause of pain and infertility affecting millions of women globally. Herein, we characterize variation in DNA methylation (DNAm) and its association with menstrual cycle phase, endometriosis, and genetic variants through analysis of genotype data and methylation in endometrial samples from 984 deeply-phenotyped participants. We estimate that 15.4% of the variation in endometriosis is captured by DNAm and identify significant differences in DNAm profiles associated with stage III/IV endometriosis, endometriosis sub-phenotypes and menstrual cycle phase, including opening of the window for embryo implantation. Menstrual cycle phase was a major source of DNAm variation suggesting cellular and hormonally-driven changes across the cycle can regulate genes and pathways responsible for endometrial physiology and function. DNAm quantitative trait locus (mQTL) analysis identified 118,185 independent cis -mQTLs including 51 associated with risk of endometriosis, highlighting candidate genes contributing to disease risk. Our work provides functional evidence for epigenetic targets contributing to endometriosis risk and pathogenesis. Data generated serve as a valuable resource for understanding tissue-specific effects of methylation on endometrial biology in health and disease.

Uterine leiomyomata (UL) are the most common tumours of the female genital tract and the primary cause of surgical removal of the uterus. Genetic factors contribute to UL susceptibility. To add understanding to the heritable genetic risk factors, we conduct a genome-wide association study (GWAS) of UL in up to 426,558 European women from FinnGen and a previous UL meta-GWAS. In addition to the 50 known UL loci, we identify 22 loci that have not been associated with UL in prior studies. UL-associated loci harbour genes enriched for development, growth, and cellular senescence. Of particular interest are the smooth muscle cell differentiation and proliferation-regulating genes functioning on the myocardin-cyclin dependent kinase inhibitor 1 A pathway. Our results further suggest that genetic predisposition to increased fat-free mass may be causally related to higher UL risk, underscoring the involvement of altered muscle tissue biology in UL pathophysiology. Overall, our findings add to the understanding of the genetic pathways underlying UL, which may aid in developing novel therapeutics.