Pleiotropy may contribute to adverse mental health outcomes in women with endometriosis

Women with endometriosis faced higher odds of anxiety, depression and eating disorders, which researchers said are likely driven by genetic and phenotypic associations.

Dora Koller, PhD, MSc, Marie Curie Postdoctoral Fellow at Yale University School of Medicine, and colleagues conducted a genetic association study to better understand if pleiotropy — when one gene produces two or more seemingly unrelated effects — is responsible for the association between endometriosis and anxiety, depression and eating disorders.

“The association between endometriosis and depression and anxiety has been previously linked to chronic pain. Although chronic pain surely plays an important role underlying these associations, it is not the sole factor,” the researchers wrote in JAMA Network Open.

Koller and Renato Polimanti, PhD, MSc, an associate professor of psychiatry at Yale University School of Medicine and coauthor of the study, told Healio that the study is important for primary care providers because they may be able to identify people who have endometriosis and are showing signs of poor mental health.

“These individuals could receive care not only to manage their pain and other physical symptoms of endometriosis, but also for their comorbid mental health conditions, such as depression, anxiety and eating disorders. This could include referral to specialist physicians,” they said.

Koller, Polimanti and colleagues conducted the study, which included 202,276 unrelated female participants, from Sept. 13, 2021, to June 24, 2022. They combined U.K. Biobank genotypic and phenotypic information with genome-wide association statistics from the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium (five countries), the FinnGen study (Finland), the Million Veteran Program (United States) and the Psychiatric Genomics Consortium (11 countries).

The researchers assessed data from 8,276 women with endometriosis who had a mean age of 53.1 years and 194,000 control participants who had a mean age of 56.7 years. They used multiple regression models that accounted for different sets of covariates to assess differences in sociodemographic characteristics and endometriosis symptoms.

After accounting for age, BMI, chronic pain-related phenotypes, irritable bowel syndrome and psychiatric comorbidities, Koller, Polimanti and colleagues found that endometriosis was associated with higher odds of anxiety (OR = 2.61; 95% CI, 2.30-2.97), depression (OR = 3.61; 95% CI, 3.32-3.92) and eating disorders (OR = 2.94; 95% CI, 1.96-4.41).

“This study contributes to the increasing evidence that endometriosis is a systemic disease that affects women’s mental and physical health,” the researchers wrote.

The associations were additionally supported by consistent genetic correlations, according to Koller, Polimanti and colleagues.

The researchers conducted a one-sample Mendelian randomization to investigate causal associations. They found that genetic liabilities to anxiety (OR = 1.39) and depression (OR = 1.09), but not eating disorders, were associated with higher odds of endometriosis.

Koller, Polimanti and colleagues also conducted a genome-wide analysis of pleiotropic associations. They identified one locus — DGKB rs12666606 — that had evidence of pleiotropy between depression and endometriosis.

“Our genetic and phenotypic analyses included a wide range of covariates to account for the possible effects of variables ... that could affect the associations identified,” they wrote. “Accordingly, our findings highlight that pleiotropy likely contributes to the adverse mental health outcomes observed in women affected by endometriosis independently of known risk factors and possible confounders.”

Koller and Polimanti told Healio the study “highlighted that the comorbidity between endometriosis and certain psychiatric disorders is partially due to genetic factors and is not fully explained by chronic pain associated with endometriosis symptoms.”

“Additionally, because of the shared genetics between endometriosis and psychiatric disorders, in the near future, we may be able to predict which patients with endometriosis are more likely to develop psychiatric comorbidities using genetics as a tool. This could lead to better prevention and treatment strategies,” they said.

In what is, to their knowledge, the first large-scale study to offer phenotypic and genetic evidence of processes involved in endometriosis’ psychiatric comorbidities, Koller, Polimanti and colleagues concluded that their findings “highlight that endometriosis is associated with women’s mental health through pleiotropic mechanisms.”

“These phenotypic associations were in line with the genetic correlation of endometriosis with depression, anxiety, and eating disorders,” they wrote. “In addition to possible shared associations, both depression and anxiety may be associated with the risk of endometriosis, although we lacked the statistical power to test this.”

Koller and Polimanti said that it is critical to raise awareness about endometriosis among primary care providers and specialists, such as psychiatrists.

“Seeing it as a disease affecting more than just the female reproductive system can help patients manage their symptoms and comorbidities early,” they said.