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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.

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.

Endometriosis is a heritable hormone-dependent gynecological disorder, associated with severe pelvic pain and reduced fertility; however, its molecular mechanisms remain largely unknown. Here we perform a meta-analysis of 11 genome-wide association case-control data sets, totalling 17,045 endometriosis cases and 191,596 controls. In addition to replicating previously reported loci, we identify five novel loci significantly associated with endometriosis risk (P

Birth weight (BW) has been shown to be influenced by both fetal and maternal factors and in observational studies is reproducibly associated with future risk of adult metabolic diseases including type 2 diabetes (T2D) and cardiovascular disease. These life-course associations have often been attributed to the impact of an adverse early life environment. Here, we performed a multi-ancestry genome-wide association study (GWAS) meta-analysis of BW in 153,781 individuals, identifying 60 loci where fetal genotype was associated with BW (P

Author(s): Samvida S. Venkatesh, Teresa Ferreira, Stefania Benonisdottir, Nilufer Rahmioglu, Christian M. Becker, Ingrid Granne, Krina T. Zondervan, Michael V. Holmes, Cecilia M. Lindgren, Laura B. L. Wittemans Reference 45 [...]

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 underrepresented 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. [ABSTRACT FROM AUTHOR]

Background Obesity is observationally associated with altered risk of many female reproductive conditions. These include polycystic ovary syndrome (PCOS), abnormal uterine bleeding, endometriosis, infertility, and pregnancy-related disorders. However, the roles and mechanisms of obesity in the aetiology of reproductive disorders remain unclear. Thus, we aimed to estimate observational and genetically predicted causal associations between obesity, metabolic hormones, and female reproductive disorders. Methods and findings Logistic regression, generalised additive models, and Mendelian randomisation (MR) (2-sample, non-linear, and multivariable) were applied to obesity and reproductive disease data on up to 257,193 women of European ancestry in UK Biobank and publicly available genome-wide association studies (GWASs). Body mass index (BMI), waist-to-hip ratio (WHR), and WHR adjusted for BMI were observationally (odds ratios [ORs] = 1.02-1.87 per 1-SD increase in obesity trait) and genetically (ORs = 1.06-2.09) associated with uterine fibroids (UF), PCOS, heavy menstrual bleeding (HMB), and pre-eclampsia. Genetically predicted visceral adipose tissue (VAT) mass was associated with the development of HMB (OR [95% CI] per 1-kg increase in predicted VAT mass = 1.32 [1.06-1.64], P = 0.0130), PCOS (OR [95% CI] = 1.15 [1.08-1.23], P = 3.24 x 10.sup.-05 ), and pre-eclampsia (OR [95% CI] = 3.08 [1.98-4.79], P = 6.65 x 10.sup.-07). Increased waist circumference posed a higher genetic risk (ORs = 1.16-1.93) for the development of these disorders and UF than did increased hip circumference (ORs = 1.06-1.10). Leptin, fasting insulin, and insulin resistance each mediated between 20% and 50% of the total genetically predicted association of obesity with pre-eclampsia. Reproductive conditions clustered based on shared genetic components of their aetiological relationships with obesity. This study was limited in power by the low prevalence of female reproductive conditions among women in the UK Biobank, with little information on pre-diagnostic anthropometric traits, and by the susceptibility of MR estimates to genetic pleiotropy. Conclusions We found that common indices of overall and central obesity were associated with increased risks of reproductive disorders to heterogenous extents in a systematic, large-scale genetics-based analysis of the aetiological relationships between obesity and female reproductive conditions. Our results suggest the utility of exploring the mechanisms mediating the causal associations of overweight and obesity with gynaecological health to identify targets for disease prevention and treatment., Author(s): Samvida S. Venkatesh 1,2,*, Teresa Ferreira 1,3, Stefania Benonisdottir 1, Nilufer Rahmioglu 2,3, Christian M. Becker 3, Ingrid Granne 3, Krina T. Zondervan 2,3, Michael V. Holmes 4,5, Cecilia [...]

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. [ABSTRACT FROM AUTHOR]

Evidence from observational studies indicates that endometriosis and depression often co-occur. However, conflicting evidence exists, and the etiology as well as biological mechanisms underlying their comorbidity remain unknown. Utilizing genome-wide association study (GWAS) data, we comprehensively assessed the relationship between endometriosis and depression. Single nucleotide polymorphism effect concordance analysis (SECA) found a significant genetic overlap between endometriosis and depression (PFsig-permuted = 9.99 × 10−4). Linkage disequilibrium score regression (LDSC) analysis estimated a positive and highly significant genetic correlation between the two traits (rG = 0.27, P = 8.85 × 10−27). A meta-analysis of endometriosis and depression GWAS (sample size = 709,111), identified 20 independent genome-wide significant loci (P < 5 × 10−8), of which eight are novel. Mendelian randomization analysis (MR) suggests a causal effect of depression on endometriosis. Combining gene-based association results across endometriosis and depression GWAS, we identified 22 genes with a genome-wide significant Fisher's combined P value (FCPgene < 2.75 × 10−6). Genes with a nominal gene-based association (Pgene < 0.05) were significantly enriched across endometriosis and depression (Pbinomial-test = 2.90 × 10−4). Also, genes overlapping the two traits at Pgene < 0.1 (Pbinomial-test = 1.31 × 10−5) were significantly enriched for the biological pathways 'cell–cell adhesion', 'inositol phosphate metabolism', 'Hippo-Merlin signaling dysregulation' and 'gastric mucosa abnormality'. These results reveal a shared genetic etiology for endometriosis and depression. Indeed, additional analyses found evidence of a causal association between each of endometriosis and depression and at least one abnormal condition of gastric mucosa. Our study confirms the comorbidity of endometriosis and depression, implicates links with gastric mucosa abnormalities in their causal pathways and reveals potential therapeutic targets for further investigation. [ABSTRACT FROM AUTHOR]