Genetic Overlap Between Endometriosis and Autoimmune Disorders

Comprehensive immunogenetic profiling uncovers overlapping inflammatory pathways and shared risk loci in endometriosis.

Key Points

Highlights:

• Women with endometriosis have a significantly higher risk of several autoimmune, autoinflammatory, and mixed-pattern immune diseases.
• Genetic correlation analyses show shared genetic architecture between endometriosis and osteoarthritis, rheumatoid arthritis, and multiple sclerosis.

Importance:

• Understanding the shared phenotypic and genetic links between endometriosis and immune-mediated conditions provides a biological basis for comorbidity, informs risk counseling, highlights the need for clinical vigilance, and may guide future therapeutic strategies—including repurposing of immunomodulatory drugs.

What's Done Here?

• The authors analyzed 273,404 UK Biobank females using both retrospective cohort and cross-sectional designs to determine phenotypic associations between endometriosis and 31 immunological diseases.
• They conducted the first female-specific GWAS for immune conditions and integrated these results with the largest available GWAS meta-analyses.
• Genetic correlation (LDSC), Mendelian randomization, and multi-trait GWAS (MTAG) were used to test shared genetic risk and potential causal pathways.
• Mapping across pathways and enrichment analyses identified overlapping biological processes.

Key Results:

• Endometriosis was associated with a 30–80% increased risk of rheumatoid arthritis, multiple sclerosis, coeliac disease, psoriasis, and osteoarthritis.
• Significant genetic correlations were found with "Osteoarthritis", "Rheumatoid arthritis", Multiple sclerosis.
• Mendelian randomization suggested a causal link between endometriosis and rheumatoid arthritis.
• MTAG identified six novel endometriosis loci, and four shared genetic loci with osteoarthritis and/or rheumatoid arthritis.
• Shared pathways included innate and adaptive immunity, ECM organization, leukocyte migration, lipid and arachidonic acid metabolism.

 Strengths and Limitations:

• Strengths are uniquely large-scale, multi-layer analysis integrating UK Biobank phenotypes, female-specific and meta-analyzed GWAS, MR, and pathway-based functional annotation, providing the strongest evidence to date for shared biological mechanisms between endometriosis and immune disorders.
• Limitations are : Female-specific GWAS were underpowered, shared loci require experimental validation, MR instruments explained a small proportion of trait variance, and undiagnosed endometriosis in UK Biobank may bias phenotypic estimates toward the null.

From the Editor-in-Chief – EndoNews

"This comprehensive analysis marks a significant advance in reframing endometriosis as a systemic immunoinflammatory condition rather than a disorder limited to the reproductive tract. By pairing large-scale UK Biobank data with multi-layer genomic analyses, the authors provide compelling evidence that endometriosis shares both clinical comorbidity and genetic architecture with multiple immune-mediated diseases.

The identification of a potential causal link to rheumatoid arthritis is particularly thought-provoking. Although modest in effect size, it validates a long-recognized clinical pattern: women with endometriosis frequently experience symptoms that extend beyond pelvic disease, including fatigue, widespread pain, and inflammatory overlap. These data reinforce the need for clinicians to adopt a broader, multisystem perspective when evaluating and managing endometriosis.

Beyond epidemiology, the genomic findings reveal convergence across pathways involving innate and adaptive immunity, extracellular matrix remodeling, leukocyte migration, and lipid metabolism. These mechanistic insights support the concept of endometriosis as a chronic inflammatory state emerging from immune dysregulation, challenging the outdated view that it is primarily an estrogen-driven gynecologic condition.

At the same time, the results should be interpreted with caution. Genetic correlation does not equate to deterministic risk, and Mendelian randomization findings—while intriguing—require experimental validation. Underdiagnosis of endometriosis in population cohorts likely attenuates the true magnitude of these associations. Still, the consistency across phenotypic, genetic, and pathway-based analyses gives these findings substantial credibility.

Altogether, this work expands the conceptual framework of endometriosis and opens avenues for precision medicine, including improved risk prediction, more accurate patient stratification, and potential repurposing of immunomodulatory therapies for selected subgroups. It represents a significant step toward understanding endometriosis within a broader systemic and immunological context."

Lay Summary

Women with endometriosis may face a higher risk of developing several immune-related conditions, according to a large study led by Rahmioglu and Zondervan, published in Human Reproduction. Using data from more than 270,000 women in the UK Biobank, the researchers examined whether endometriosis is linked to autoimmune and inflammatory diseases, and whether these connections might reflect underlying shared biological mechanisms.

The team found that women with endometriosis were more likely to have conditions such as rheumatoid arthritis, osteoarthritis, multiple sclerosis, psoriasis, and coeliac disease. To understand why these associations occur, the researchers combined large-scale population data with genetic information from several major genome-wide association studies. Their analyses revealed that endometriosis and multiple immune diseases share common genetic risk factors, particularly in pathways related to inflammation, immune-cell activity, extracellular matrix remodeling, and lipid metabolism.

One of the most striking observations was evidence suggesting a potential causal relationship between endometriosis and rheumatoid arthritis. Several genetic regions were found to increase the risk of both conditions, strengthening the idea that they may arise from partially overlapping biological processes.

These findings provide a biological explanation for why many women with endometriosis report systemic symptoms and why immune and inflammatory features often coexist. The study also highlights the need for clinicians to be alert to potential comorbid immune conditions when caring for patients with endometriosis. While experimental studies are still needed to clarify the exact mechanisms involved, this work lays an important foundation for future research into precision therapies and improved risk assessment.

Research Source: https://pubmed.ncbi.nlm.nih.gov/40262193/