Epidemiologic and Genetic Associations of Endometriosis With Depression, Anxiety, and Eating Disorders

Abstract

Importance: Endometriosis is a common chronic gynecologic pathology with a large negative impact on women's health. Beyond severe physical symptoms, endometriosis is also associated with several psychiatric comorbidities, including depression and anxiety.

Objective: To investigate whether pleiotropy contributes to the association of endometriosis with depression, anxiety, and eating disorders.

Design, setting, and participants: This genetic association study was performed between September 13, 2021, and June 24, 2022, in 202 276 unrelated female participants. Genotypic and phenotypic information from the UK Biobank was combined with genome-wide association statistics available from the Psychiatric Genomics Consortium (11 countries), the Million Veteran Program (US), the FinnGen study (Finland), and the CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) consortium (5 countries).

Main outcomes and measures: The main outcomes were the phenotypic and genetic associations of endometriosis with anxiety, depression, and eating disorders.

Results: A total of 8276 women with endometriosis (mean [SD] age, 53.1 [7.9] years) and 194 000 female controls (mean [SD] age, 56.7 [7.9] years) were included in the study. In a multivariate regression analysis accounting for age, body mass index, socioeconomic status, chronic pain-related phenotypes, irritable bowel syndrome, and psychiatric comorbidities, endometriosis was associated with increased odds of depression (odds ratio [OR], 3.61; 95% CI, 3.32-3.92), eating disorders (OR, 2.94; 95% CI, 1.96-4.41), and anxiety (OR, 2.61; 95% CI, 2.30-2.97). These associations were supported by consistent genetic correlations (rg) (depression rg, 0.36, P = 1.5 × 10-9; anxiety rg, 0.33, P = 1.17 × 10-5; and eating disorders rg, 0.61, P = .02). With the application of a 1-sample mendelian randomization, the genetic liabilities to depression and anxiety were associated with increased odds of endometriosis (depression: OR, 1.09; 95% CI, 1.08-1.11; anxiety: OR, 1.39; 95% CI, 1.13-1.65). A genome-wide analysis of pleiotropic associations shared between endometriosis and psychiatric disorders identified 1 locus, DGKB rs12666606, with evidence of pleiotropy between endometriosis and depression after multiple testing correction (z = -9.46 for endometriosis, z = 8.10 for depression, P = 5.56 × 10-8; false discovery rate q = 4.95 × 10-4).

Conclusions and relevance: These findings highlight that endometriosis is associated with women's mental health through pleiotropic mechanisms. To our knowledge, this is the first large-scale study to provide genetic and phenotypic evidence of the processes underlying the psychiatric comorbidities of endometriosis.

Figure 1.. Study Overview

A logistic regression analysis was performed to investigate whether psychiatric phenotypes are associated with endometriosis after accounting for multiple variables. Genetic correlation, mendelian randomization, and pleiotropy analyses were performed to study the genetic overlap between endometriosis and psychiatric traits. CHARGE indicates Cohorts for Heart and Aging Research in Genomic Epidemiology; MVP, Million Veteran Program; and PGC, Psychiatric Genomics Consortium.

Figure 2.. Genetic Correlation Among Traits and Cohorts Investigated in the Study

A, Genetic correlation between endometriosis and depression, anxiety, and eating disorders using the Scalable Genetic Correlation Estimator (SCORE) with UK Biobank (UKB) individual-level genotype data with age and the first 10 principal components as covariates and additionally adding the other 2 traits as covariates. Whiskers represent standard errors. B, Genetic correlation across all traits and cohorts using linkage disequilibrium score regression (LDSC) with genome-wide association study summary statistics. CHARGE indicates Cohorts for Heart and Aging Research in Genomic Epidemiology; CRP, C-reactive protein; MVP, Million Veteran Program; PGC, Psychiatric Genomics Consortium; and rg, genetic correlation.

Figure 3.. One-Sample Mendelian Randomization Analysis With Endometriosis as Outcome and Endometriosis as Exposure

Bidirectional 1-sample mendelian randomization analyses were performed to examine the association between endometriosis and depression, anxiety, and eating disorders. OR indicates odds ratio.