title: Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome.
abstract: 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.
authors.affiliation: 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.
authors.forename: Felix R
authors.identifier: http://orcid.org/0000-0003-3789-7651
authors.initials: FR
authors.lastname: Day
authors.affiliation: 23andMe Inc., Mountain View, California 94043, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: 23andMe Inc., Mountain View, California 94043, USA.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
authors.forename: Lisette
authors.initials: L
authors.lastname: Stolk
authors.affiliation: deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Unnur
authors.identifier: http://orcid.org/0000-0001-8146-8278
authors.initials: U
authors.lastname: Styrkarsdottir
authors.affiliation: Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Richa
authors.initials: R
authors.lastname: Saxena
authors.affiliation: Department of Anaesthesia and Center for Human Genetic Research, Massachusetts General Hospital, Boston, Massachusetts 02114, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Bjonnes
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
authors.forename: Linda
authors.initials: L
authors.lastname: Broer
authors.affiliation: Department of Paediatrics, University of Cambridge School of Clinical Medicine, Box 181, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: David B
authors.identifier: http://orcid.org/0000-0002-2566-9304
authors.initials: DB
authors.lastname: Dunger
authors.affiliation: deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.|Institute of Biomedical and Neural Engineering, School of Science and Engineering, Reykjavík University, Menntavegur 1, 101 Reykjavík, Iceland.
authors.forename: Bjarni V
authors.initials: BV
authors.lastname: Halldorsson
authors.affiliation: 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.
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.affiliation: Human Evolutionary Genetics, CNRS URA3012 Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris Cedex 15, France.
authors.forename: Guillaume
authors.initials: G
authors.lastname: Laval
authors.affiliation: Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: Iain
authors.initials: I
authors.lastname: Mathieson
authors.affiliation: School of Social and Community Medicine, University of Bristol, Oakfield House, Bristol BS8 2BN, UK.
authors.forename: Wendy L
authors.initials: WL
authors.lastname: McCardle
authors.affiliation: Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, 3015 GE, The Netherlands.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Louwers
authors.affiliation: Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, 3015 GE, The Netherlands.
authors.forename: Cindy
authors.initials: C
authors.lastname: Meun
authors.affiliation: 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.
authors.forename: Susan
authors.initials: S
authors.lastname: Ring
authors.affiliation: 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.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Scott
authors.affiliation: deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.
authors.forename: Patrick
authors.identifier: http://orcid.org/0000-0001-7123-6123
authors.initials: P
authors.lastname: Sulem
authors.affiliation: Department of Internal Medicine, Erasmus MC, Rotterdam 3015 GE, The Netherlands.
authors.forename: André G
authors.initials: AG
authors.lastname: Uitterlinden
authors.affiliation: 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.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Wareham
authors.affiliation: deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Unnur
authors.initials: U
authors.lastname: Thorsteinsdottir
authors.affiliation: Division of Endocrinology, Metabolism and Diabetes, University of Utah School of Medicine, Salt Lake City, Utah 84112, USA.
authors.forename: Corrine
authors.initials: C
authors.lastname: Welt
authors.affiliation: deCODE Genetics/Amgen, Sturlugata 8, IS-101 Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, IS-101 Reykjavik, Iceland.
authors.forename: Kari
authors.initials: K
authors.lastname: Stefansson
authors.affiliation: Division of Reproductive Medicine, Department of Obstetrics and Gynaecology, Erasmus MC, Rotterdam, 3015 GE, The Netherlands.
authors.forename: Joop S E
authors.initials: JSE
authors.lastname: Laven
authors.affiliation: 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.|Department of Paediatrics, University of Cambridge School of Clinical Medicine, Box 181, Cambridge Biomedical Campus, Cambridge CB2 0QQ, UK.
authors.forename: Ken K
authors.initials: KK
authors.lastname: Ong
authors.affiliation: 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.
authors.forename: John R B
authors.initials: JRB
authors.lastname: Perry
mesh_terms: D017766:Acid Anhydride Hydrolases; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000375:Aging / Q000502:physiology; D016022:Case-Control Studies; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D037201:Follicle Stimulating Hormone, beta Subunit / Q000235:genetics; D055106:Genome-Wide Association Study; D006801:Humans; D009363:Neoplasm Proteins / Q000235:genetics; D010053:Ovary / Q000502:physiology; D010750:Phosphoproteins / Q000235:genetics; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D012641:Selection, Genetic; D014157:Transcription Factors; D044465:White People / Q000235:genetics*; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D037201:Follicle Stimulating Hormone, beta Subunit; D009363:Neoplasm Proteins; D010750:Phosphoproteins; C477698:THADA protein, human; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human; D066246:ErbB Receptors; D017766:Acid Anhydride Hydrolases; C112158:RAD50 protein, human; D045643:DNA Repair Enzymes