Deciphering the Complex Genetic Associations Between Endometriosis and Psychiatric Comorbidities: A Comprehensive Analysis

Endometriosis is a debilitating gynecological condition characterized by the abnormal growth of endometrial tissue outside the uterus. It affects millions of women worldwide and is associated with a myriad of physical symptoms, such as chronic pelvic pain, dysmenorrhea, and infertility.

However, emerging evidence suggests that endometriosis may also have significant implications for mental health, with increased prevalence rates of psychiatric comorbidities, including depression, anxiety, and eating disorders.

Understanding the underlying genetic and phenotypic associations between endometriosis and these mental health conditions could pave the way for improved diagnostic and therapeutic approaches.

In this comprehensive study, we explore the intricate relationships between endometriosis and psychiatric comorbidities, considering a wide range of covariates and utilizing multiple analytical methods.

Methodology

To investigate the genetic and phenotypic associations, we conducted a large-scale genetic association study utilizing data from various cohorts, including the UK Biobank (UKB) and the independent FinnGen cohort. The study cohort comprised women with self-reported and clinically diagnosed endometriosis cases.

Our analysis included a diverse array of covariates to account for potential confounding factors, such as age, body mass index, socioeconomic status, age at menarche, length of menstrual cycle, irritable bowel syndrome, contraceptive medication use, and several pain-related phenotypes.

Findings

• Differential Associations Between Endometriosis and Psychiatric Comorbidities

Intriguingly, our analysis revealed that eating disorders were associated with higher odds of endometriosis compared to depression and anxiety when accounting for multiple covariates.

However, when considering psychiatric comorbidities alongside these covariates, endometriosis demonstrated a stronger association with depression. This suggests that specific factors may contribute to different mental health outcomes in endometriosis patients.

• Chronic Pain as a Mediator of Psychiatric Comorbidities

Chronic pain is a hallmark symptom of endometriosis, affecting patients regardless of their menstrual cycle phase. The continuous and severe pain experienced by these women can lead to a myriad of physical and psychological challenges. Indeed, clinical studies have shown that chronic pelvic pain in endometriosis patients is strongly linked to increased rates of depression and other psychiatric comorbidities.

However, our findings indicate that while chronic pain may partially account for the heightened odds of anxiety, depression, and eating disorders in endometriosis cases, it does not fully explain the observed associations. This suggests the presence of additional disease-specific factors contributing to the mental health burden in endometriosis patients.

• Genetic Correlations Between Endometriosis and Psychiatric Disorders

Through two different analytical methods, LDSC and SCORE, we explored the genetic correlations between endometriosis and depression, anxiety, and eating disorders. The results revealed a particularly robust genetic correlation between endometriosis and eating disorders, which aligned with the strength of the observed phenotypic associations.

Even after controlling for comorbid psychiatric conditions, the genetic correlations remained significant, indicating that there are unique genetic factors contributing to the pleiotropy of endometriosis with depression, anxiety, and eating disorders.

• Pleiotropic Variant DGKB rs12666606 and its Implications

Our genome-wide analysis identified the DGKB rs12666606 variant as a key pleiotropic genetic variant linking endometriosis with depression. The DGKB gene encodes diacylglycerol kinase, an enzyme involved in the conversion of diacylglycerol to phosphatidic acid and phosphatidate.

Additionally, diacylglycerol kinase ζ enzymes play essential roles in inflammatory and immune responses by regulating nuclear factor–κB, which is a pivotal component involved in inflammation, immune responses, apoptosis, and oncogenesis. Interestingly, altered DGKB activity could also influence the breakdown of diacylglycerol and, subsequently, the production of estradiol, a hormone central to endometriosis progression.

This suggests that molecular pathways associated with DGKB could provide valuable insights into the shared genetic mechanisms underlying endometriosis and depression.

Conclusion

This comprehensive genetic association study has unveiled new insights into the complex relationships between endometriosis and psychiatric comorbidities. The presence of pleiotropy suggests shared genetic factors contributing to the adverse mental health outcomes observed in women with endometriosis.

The influence of chronic pain, although significant, does not entirely account for the increased odds of anxiety, depression, and eating disorders in these patients. Further investigations into the association between inflammation and endometriosis, as well as its implications for psychiatric comorbidities, are warranted.

Additionally, the identification of the pleiotropic variant DGKB rs12666606 and its associated molecular pathways offers a promising avenue for future research and potential therapeutic targets.

As we continue to unravel the intricate genetic and phenotypic associations between endometriosis and psychiatric comorbidities, we can strive to enhance the care and quality of life for women affected by this complex and challenging condition.

reference link : https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2800556