Please use this identifier to cite or link to this item:
Scopus Web of Science® Altmetric
Type: Journal article
Title: Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome
Author: Day, F.
Hinds, D.
Tung, J.
Stolk, L.
Styrkarsdottir, U.
Saxena, R.
Bjonnes, A.
Broer, L.
Dunger, D.
Halldorsson, B.
Lawlor, D.
Laval, G.
Mathieson, I.
McCardle, W.
Louwers, Y.
Meun, C.
Ring, S.
Scott, R.
Sulem, P.
Uitterlinden, A.
et al.
Citation: Nature Communications, 2015; 6(1):8464-1-8464-7
Publisher: Nature Publishing Group
Issue Date: 2015
ISSN: 2041-1723
Statement of
Felix R. Day, David A. Hinds, Joyce Y. Tung, Lisette Stolk, Unnur Styrkarsdottir, Richa Saxena, Andrew Bjonnes, Linda Broer, David B. Dunger, Bjarni V. Halldorsson, Debbie A. Lawlor, Guillaume Laval, Iain Mathieson, Wendy L. McCardle, Yvonne Louwers, Cindy Meun, Susan Ring, Robert A. Scott, Patrick Sulem, André G. Uitterlinden, Nicholas J. Wareham, Unnur Thorsteinsdottir, Corrine Welt, Kari Stefansson, Joop S. E. Laven, Ken K. Ong, John R. B. Perry
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.
Keywords: Ovary
Polycystic Ovary Syndrome
Follicle Stimulating Hormone, beta Subunit
DNA Repair Enzymes
Acid Anhydride Hydrolases
Adaptor Proteins, Signal Transducing
DNA-Binding Proteins
Neoplasm Proteins
Transcription Factors
Case-Control Studies
European Continental Ancestry Group
Genome-Wide Association Study
Selection, Genetic
ErbB Receptors
Rights: © 2015 Macmillan Publishers Limited. All rights reserved. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit
DOI: 10.1038/ncomms9464
Appears in Collections:Aurora harvest 7
Medicine publications

Files in This Item:
File Description SizeFormat 
hdl_99207.pdfPublished version467.99 kBAdobe PDFView/Open

Items in DSpace are protected by copyright, with all rights reserved, unless otherwise indicated.