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. 2015 Sep 29:6:8464.
doi: 10.1038/ncomms9464.

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

Felix R Day  1 , David A Hinds  2 , Joyce Y Tung  2 , Lisette Stolk  3 , Unnur Styrkarsdottir  4 , Richa Saxena  5 , Andrew Bjonnes  5 , Linda Broer  3 , David B Dunger  6 , Bjarni V Halldorsson  4   7 , Debbie A Lawlor  8   9 , Guillaume Laval  10 , Iain Mathieson  11 , Wendy L McCardle  9 , Yvonne Louwers  12 , Cindy Meun  12 , Susan Ring  8   9 , Robert A Scott  1 , Patrick Sulem  4 , André G Uitterlinden  3 , Nicholas J Wareham  1 , Unnur Thorsteinsdottir  4   13 , Corrine Welt  14 , Kari Stefansson  4   13 , Joop S E Laven  12 , Ken K Ong  1   6 , John R B Perry  1
Affiliations

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

Felix R Day et al. Nat Commun. .

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.

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Conflict of interest statement

D.A.H. and J.Y.T. are employees of and own stock or stock options in 23andMe, Inc. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1. Manhattan and QQ plots displaying PCOS genome-wide association results.
Results shown are from discovery phase only.
Figure 2
Figure 2. Scatter plots of the associations between four significant intermediate traits.
Panels show (a) BMI, (b) age at menopause, (c) SHBG and (d) insulin resistance, in each case showing the associations between the SNP and the trait of interest, and the odds ratio for PCOS for that SNP, with the attendant 95% confidence intervals.
See this image and copyright information in PMC

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