Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome
Open accessAbstract
Polycystic ovary syndrome (PCOS) is the most common reproductive disorder in women, yet there is little consensus regarding its aetiology. Here we perform a genome-wide association study of PCOS in up to 5,184 self-reported cases of White European ancestry and 82,759 controls, with follow-up in a further ∼2,000 clinically validated cases and ∼100,000 controls. We identify six signals for PCOS at genome-wide statistical significance (P<5 × 10(-8)), in/near genes ERBB4/HER4, YAP1, THADA, FSHB, RAD50 and KRR1. Variants in/near three of the four epidermal growth factor receptor genes (ERBB2/HER2, ERBB3/HER3 and ERBB4/HER4) are associated with PCOS at or near genome-wide significance. Mendelian randomization analyses indicate causal roles in PCOS aetiology for higher BMI (P=2.5 × 10(-9)), higher insulin resistance (P=6 × 10(-4)) and lower serum sex hormone binding globulin concentrations (P=5 × 10(-4)). Furthermore, genetic susceptibility to later menopause is associated with higher PCOS risk (P=1.6 × 10(-8)) and PCOS-susceptibility alleles are associated with higher serum anti-Müllerian hormone concentrations in girls (P=8.9 × 10(-5)). This large-scale study implicates an aetiological role of the epidermal growth factor receptors, infers causal mechanisms relevant to clinical management and prevention, and suggests balancing selection mechanisms involved in PCOS risk.
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Differences in study or subject characteristics (including inherent problems in analysing and reporting clamp data, recruitment strategies, ethnicity and lifestyle factors) may account for some of the unexplained effects of PCOS on IR.
“Differences in study or subject characteristics, including inherent problems in analysing and reporting data from the euglycaemic-hyperinsulinaemic clamp, recruitment strategies, ethnicity and lifestyle factors (Day et al., 2015) may account for some of the unexplained effects of PCOS on IR.”
From Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies (2016) · cites this paper as Day et al., 2015
The paper discusses heterogeneity among PCOS cases (opening section; no page available) and differences between self-reported and clinically validated recruitment (Discussion; no page available). It does not discuss problems analysing or reporting euglycaemic-hyperinsulinaemic clamp data, or propose ethnicity and lifestyle differences as explanations for unexplained effects of PCOS on insulin resistance. (LLM, conf=0.83)
Experimental — accuracy not yet measuredRecent genome-wide association studies in Caucasian and Asian PCOS populations report preservation of genes across both NIH and Rotterdam criteria.
“recent genome-wide association studies in Caucasian (Day et al., 2015;Hayes et al., 2015) and Asian (Chen et al., 2011;Shi et al., 2012) PCOS populations report preservation of genes across both criteria.”
From Insulin resistance in polycystic ovary syndrome: a systematic review and meta-analysis of euglycaemic–hyperinsulinaemic clamp studies (2016) · cites this paper as Day et al., 2015
Recent genetic analyses have found the same PCOS susceptibility loci in self-reported and rigorously diagnosed women with PCOS.
“However, recent genetic analyses have found the same PCOS susceptibility loci in self-reported and rigorously diagnosed women with PCOS (38, 39).”
From Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome (2016) · cites this paper as [39]
GWASs involving women of Han Chinese and European origins have identified at least 16 susceptibility loci for PCOS.
“GWASs involving women of Han Chinese and European origins have identified at least 16 susceptibility loci for PCOS [113–116].”
From Polycystic Ovary Syndrome: Pathophysiology, Presentation, and Treatment With Emphasis on Adolescent Girls (2019) · cites this paper as [116]
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- Authors
- Day, F. R., Hinds, D. A., Tung, J. Y., Stolk, L., Styrkarsdottir, U., Saxena, R., Bjonnes, A., Broer, L., Dunger, D. B., Halldorsson, B. V., Lawlor, D. A., Laval, G., Mathieson, I., McCardle, W. L., Louwers, Y., Meun, C., Ring, S., Scott, R. A., Sulem, P., Uitterlinden, A. G., Wareham, N. J., Thorsteinsdottir, U., Welt, C., Stefansson, K., Laven, J. S. E., Ong, K. K., & Perry, J. R. B.
- Affiliations
- University of Cambridge (GB)
- 23andMe (United States) (US)
- Erasmus MC (NL)
- Massachusetts General Hospital (US)
- University of Bristol (GB)
- Centre National de la Recherche Scientifique (FR)
- Harvard University (US)
- deCODE Genetics (Iceland) (IS)
- University of Utah (US)
- Corresponding author
- Ong, Ken K.
- Perry, John R. B.
- ORCID
- Day, Felix R.
- Hinds, David A.
- Tung, Joyce Y.
- Styrkarsdottir, Unnur
- Saxena, Richa
- Broer, Linda
- Dunger, David B.
- Lawlor, Debbie A.
- Laval, Guillaume
- Mathieson, Iain
- Louwers, Yvonne
- Meun, Cindy
- Ring, Susan
- Sulem, Patrick
- Uitterlinden, André G.
- Wareham, Nicholas J.
- Welt, Corrine
- Laven, Joop S. E.
- Ong, Ken K.
- Perry, John R. B.
- Venue
- Nature Communications
- Published
- 2015-09-29
- Volume
- 6
- Issue
- 1
- Pages
- 8464-8464
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC4598835
- OpenAlex
- W2186418777
- Cited by
- 459
- References
- 50
- Citations by year
- 2026: 24 · 2025: 33 · 2024: 48 · 2023: 93 · 2022: 48 · 2021: 42 · 2020: 35 · 2019: 40 · 2018: 44 · 2017: 24 · 2016: 24 · 2015: 2 · 2014: 1
- FWCI
- 35.75
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion, cc-by)
- Bristol Research (University of Bristol) (publishedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion, cc-by)
- RePEc: Research Papers in Economics (submittedVersion)
- Adelaide Research & Scholarship (AR&S) (University of Adelaide) (submittedVersion, cc-by)
- Apollo (University of Cambridge) (submittedVersion, cc-by)
- Funders
- Wellcome Trust (102215, 092731)
- National Institute for Health and Care Research (NF-SI-0508-10274, NF-SI-0513-10012, NF-SI-0512-10135)
- University of Bristol (092731, MC_UU_12013, MC_UU_12013/5)
- National Institutes of Health (5r44hg006981-03, 092731)
- Medical Research Council (MC_U106179472, MC_UU_12013_5, MC_UU_12013, MC-U106179471, U106179472, MC_UU_12015/2, MC_PC_15018, 092731, MC_UU_12015/1)
- National Human Genome Research Institute (R44-HG006981)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK077659)
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (R01HD065029)
- Topics
- Health Sciences › Medicine › Reproductive Medicine › Ovarian function and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- polycystic ovary syndrome, genetic susceptibility, epidermal growth factor receptor, ErbB4, YAP, THADA, follicle-stimulating hormone beta subunit, RAD50, Mendelian randomization, causal mechanisms, insulin resistance, body mass index, sex hormone-binding globulin, menopause, anti-Müllerian hormone, balancing selection
- MeSH terms
- YAP-Signaling Proteins, Aging, DNA-Binding Proteins, Female, Humans, Neoplasm Proteins, Ovary, Phosphoproteins, Polycystic Ovary Syndrome, Selection, Genetic, Transcription Factors, Case-Control Studies, Acid Anhydride Hydrolases, Follicle Stimulating Hormone, beta Subunit, White People, DNA Repair Enzymes, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, ErbB Receptors
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