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Nat Commun. 2015 Sep 29;6:8464. doi: 10.1038/ncomms9464.

Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.

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MRC Epidemiology Unit, University of Cambridge School of Clinical Medicine, Box 285 Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
23andMe Inc., Mountain View, California 94043, USA.
Department of Internal Medicine, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.
Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
Department of Paediatrics, University of Cambridge School of Clinical Medicine, Box 181, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavík University, Menntavegur 1, 101 Reykjavík, Iceland.
MRC Integrative Epidemiology Unit at the University of Bristol, Bristol BS8 2BN, UK.
School of Social and Community Medicine, University of Bristol, Oakfield House, Bristol BS8 2BN, UK.
Human Evolutionary Genetics, CNRS URA3012 Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, 3015 GE, The Netherlands.
Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.


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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