Genetic liability for endometriosis associates with pain, inflammatory, and metabolic traits: a polygenic score analysis

Beauchamp JL, Juliane Lyng Beauchamp, Karina Banasik, Lisette J. A. Kogelman, David Westergaard, Dea Froeding Skipper, Skipper DF, Davidsson O, Olafur B. Davidsson, Sisse Rye Ostrowski, Christina Mikkelsen, Mikkelsen C, Christian Erikstrup, Erikstrup C, Bruun MT, Mie Topholm Bruun, Aagaard B, Bitten Aagaard, Pedersen OB, Ole Birger Pedersen, Sørensen E, Erik Soerensen, Henrik Ullum, Ullum H, DBDS Genomic Cosnoritum, Palle Duun Rohde, Rohde PD, Nyegaard M, Mette Nyegaard, Hansen TF, Thomas Folkmann Hansen, Henriette Svarre Nielsen, Nielsen HS
In: medRxiv · 2026 · doi:10.64898/2026.06.18.26355987 · W7165549801
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An endometriosis polygenic risk score associated with pain, inflammatory, and metabolic traits in both sexes, and persisted in women without diagnosed endometriosis, suggesting a broader genetic liability.

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This study tested whether genetic liability for endometriosis, quantified by an endometriosis polygenic risk score (PRS), also associates with pain, inflammatory, metabolic, and other comorbidities beyond diagnosed endometriosis. Using 168,238 women and 155,304 men of European ancestry from two Danish genetic studies linked to national health registers, the authors built the PRS from an independent GWAS meta-analysis and used entropy balancing with doubly robust adjustment to address selection bias, then evaluated comorbidities in both sexes. The PRS was strongly associated with endometriosis and was associated with 20 of 29 comorbidities in women; pain conditions and cardiometabolic conditions replicated in men (shared pathways), while immune-mediated conditions were seen in women only, and 17 associations persisted even among women without diagnosed endometriosis. High genetic risk also related to increased healthcare utilization and all-cause mortality, and the authors note that their register-based outcomes and PRS-derived liability limit causal interpretation. This paper is centrally about endometriosis — it assesses how an endometriosis polygenic risk score associates with pain, inflammatory, and metabolic traits across sexes.

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Abstract

Purpose Endometriosis is associated with pain, cardiometabolic, psychiatric, and immune comorbidities. We tested whether the genetic liability captured by an endometriosis polygenic risk score (PRS) extends to these comorbidities through shared pathways or operates independently of the disease. Methods In 168,238 women and 155,304 men of European ancestry from two Danish genetic studies linked to national health registers, we constructed an endometriosis PRS using LDpred2 from an independent GWAS meta-analysis (23,112 cases, 429,677 controls). Entropy balancing with doubly robust adjustment addressed selection bias. Comorbidity analyses were performed in both sexes to distinguish shared from endometriosis-specific pathways. Results The PRS was associated with endometriosis (OR 1.55 per SD, 95% CI 1.50–1.61; AUC 0.73) and with 20 of 29 comorbidities in women. Pain conditions (fibromyalgia, migraine, chronic back pain) and cardiometabolic conditions replicated in men, indicating shared pathways, whereas immune-mediated conditions associated in women only. Seventeen associations persisted in women without diagnosed endometriosis. High genetic risk was associated with increased healthcare utilisation and all-cause mortality (HR 1.05, 95% CI 1.01–1.10). Conclusion The endometriosis PRS captures a pain-inflammatory-metabolic genetic axis operating in both sexes, indicating that the genetic liability extends beyond the uterine disease and providing a rationale for targeted investigation and risk stratification.
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Abstract

Purpose Endometriosis is associated with pain, cardiometabolic, psychiatric, and immune comorbidities. We tested whether the genetic liability captured by an endometriosis polygenic risk score (PRS) extends to these comorbidities through shared pathways or operates independently of the disease.

Methods

In 168,238 women and 155,304 men of European ancestry from two Danish genetic studies linked to national health registers, we constructed an endometriosis PRS using LDpred2 from an independent GWAS meta-analysis (23,112 cases, 429,677 controls). Entropy balancing with doubly robust adjustment addressed selection bias. Comorbidity analyses were performed in both sexes to distinguish shared from endometriosis-specific pathways.

Results

The PRS was associated with endometriosis (OR 1.55 per SD, 95% CI 1.50–1.61; AUC 0.73) and with 20 of 29 comorbidities in women. Pain conditions (fibromyalgia, migraine, chronic back pain) and cardiometabolic conditions replicated in men, indicating shared pathways, whereas immune-mediated conditions associated in women only. Seventeen associations persisted in women without diagnosed endometriosis. High genetic risk was associated with increased healthcare utilisation and all-cause mortality (HR 1.05, 95% CI 1.01–1.10).

Conclusion

The endometriosis PRS captures a pain-inflammatory-metabolic genetic axis operating in both sexes, indicating that the genetic liability extends beyond the uterine disease and providing a rationale for targeted investigation and risk stratification. Competing Interest Statement The authors have declared no competing interest. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: The CHB-OCMS and DBDS have been approved by the Zealand Regional and National Committees on Health Research Ethics (SJ-989 and NVK-1900988) and the Danish Data Protection Agency (P-2022-913 and P-2019-99) I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes

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