Polygenic risk score phenome-wide association study reveals an association between endometriosis and testosterone

Isabelle M. McGrath, Grant W. Montgomery, International Endometriosis Genetics Consortium, Sally Mortlock
BMC medicine · 2023 · vol. 21(1) , pp. 482 · doi:10.1186/s12916-023-03184-z · PMID:38049874 · W4389322901
article OA: gold CC0 ⤵ 9 in-corpus citations
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⚙ AI-generated summary by claude@2026-06, 2026-06-08 ⓘ

This study used a polygenic risk score to find that genetic liability to endometriosis is associated with various health conditions and biomarkers, notably lower testosterone levels, which may causally influence endometriosis and ovarian cancer.

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⚙ AI-generated deep summary by claude@2026-06, 2026-06-10 ⓘ

McGrath et al. performed an endometriosis polygenic risk score phenome-wide association study in UK Biobank, testing whether genetic liability to endometriosis is associated with many ICD10-based diagnoses (phecodes), 34 blood/urine biomarkers, and female reproductive factors. They calculated PRS separately in European females, males, and females without an endometriosis diagnosis, then used genetic correlation and Mendelian randomisation to probe potential causal links, with a key limitation being that UK Biobank endometriosis ascertainment relies on recorded ICD codes (and excludes adenomyosis for the endometriosis case definition). They found that genetic liability to endometriosis associates with numerous comorbid conditions and biomarkers in both sexes, with sex-specific differences suggesting sex-dependent overlap pathways. Relevance to endometriosis: the paper’s primary aim and main results directly quantify pleiotropy and causal inference for endometriosis, including an identified (via Mendelian randomisation) association where lower genetic testosterone liability is linked to endometriosis.

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Abstract

BACKGROUND: Endometriosis affects 1 in 9 women, yet it is poorly understood with long diagnostic delays, invasive diagnoses, and poor treatment outcomes. Characterised by the presence of endometrial-like tissue outside of the uterus, its main symptoms are pain and infertility. Endometriosis often co-occurs with other conditions, which may provide insights into the origins of endometriosis. METHODS: Here a polygenic risk score phenome-wide association study of endometriosis was conducted in the UK Biobank to investigate the pleiotropic effects of a genetic liability to endometriosis. The relationship between the polygenic risk score for endometriosis and health conditions, blood and urine biomarkers and reproductive factors were investigated separately in females, males and females without an endometriosis diagnosis. The relationship between endometriosis and the blood and urine biomarkers was further investigated using genetic correlation and Mendelian randomisation approaches to identify causal relationships. RESULTS: Multiple health conditions, blood and urine biomarkers and reproductive factors were associated with genetic liability to endometriosis in each group, indicating many endometriosis comorbidities are not dependent on the physical manifestation of endometriosis. Differences in the associated traits between males and females highlighted the importance of sex-specific pathways in the overlap of endometriosis with many other traits. Notably, an association of genetic liability to endometriosis with lower testosterone levels was identified. Follow-up analysis utilising Mendelian randomisation approaches suggested lower testosterone may be causal for both endometriosis and clear cell ovarian cancer. CONCLUSIONS: This study highlights the diversity of the pleiotropic effects of genetic risk to endometriosis irrespective of a diagnosis of endometriosis. A key finding was the identification of a causal effect of the genetic liability to lower testosterone on endometriosis using Mendelian randomisation.

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Condition tags

mesh:D004715endometriosisinfertility

MeSH descriptors

Endometriosis Endometriosis Endometriosis Endometriosis Endometriosis Biomarkers Biomarkers Biomarkers Biomarkers Cross-Sectional Studies Cross-Sectional Studies Cross-Sectional Studies Cross-Sectional Studies Female Female Female Female Genome-Wide Association Study Genome-Wide Association Study Genome-Wide Association Study

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