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Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

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Date
2018
Author
Day, Felix
Karaderi, Tugce
Jones, Michelle R
Meun, Cindy
He, Chunyan
Drong, Alex
Kraft, Peter
Lin, Nan
Huang, Hongyan
Broer, Linda
Magi, Reedik
Saxena, Richa
Laisk-Podar, Triin
Urbanek, Margrit
Welt, Corrine K
Lindgren, Cecilia M
Franks, Steve
Thorsteinsdottir, Unnur
Stefansson, Kari
Ong, Ken
Anttila, Verneri
Neale, Benjamin M
Jarvelin, Marjo-Riitta
Hayes, Geoffrey M
Thorleifsson, Gudmar
Fernandez-Tajes, Juan
Mahajan, Anubha
Mullin, Benjamin H
Stuckey, Bronwyn G.A
Spector, Timothy D.
Wilson, Scott G
Goodarzi, Mark O
Davis, Lea
Obermeyer-Pietsch, Barbara
Uitterlinden, Andre G
Fauser, Bart
Kowalska, Irina
Visser, Jenny A
Anderson, Marianne
McCarthy, Mark I
Morin-Papunen, Laure
Salumets, Andres
Stener-Victorin, Elisabet
Ehrmann, David
Legro, Richard S
Styrkarsdottir, Unnur
Perry, John
Dunaif, Andrea
Laven, Joop S.E.
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Abstract
Polycystic ovary syndrome (PCOS) is a disorder characterized by hyperandrogenism, ovulatory dysfunction and polycystic ovarian morphology. Affected women frequently have metabolic disturbances including insulin resistance and dysregulation of glucose homeostasis. PCOS is diagnosed with two different sets of diagnostic criteria, resulting in a phenotypic spectrum of PCOS cases. The genetic similarities between cases diagnosed based on the two criteria have been largely unknown. Previous studies in Chinese and European subjects have identified 16 loci associated with risk of PCOS. We report a fixed-effect, inverse-weighted-variance meta-analysis from 10,074 PCOS cases and 103,164 controls of European ancestry and characterisation of PCOS related traits. We identified 3 novel loci (near PLGRKT, ZBTB16 and MAPRE1), and provide replication of 11 previously reported loci. Only one locus differed significantly in its association by diagnostic criteria; otherwise the genetic architecture was similar between PCOS diagnosed by self-report and PCOS diagnosed by NIH or non-NIH Rotterdam criteria across common variants at 13 loci. Identified variants were associated with hyperandrogenism, gonadotropin regulation and testosterone levels in affected women. Linkage disequilibrium score regression analysis revealed genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS. Mendelian randomization analyses suggested variants associated with body mass index, fasting insulin, menopause timing, depression and male-pattern balding play a causal role in PCOS. The data thus demonstrate 3 novel loci associated with PCOS and similar genetic architecture for all diagnostic criteria. The data also provide the first genetic evidence for a male phenotype for PCOS and a causal link to depression, a previously hypothesized comorbid disease. Thus, the genetics provide a comprehensive view of PCOS that encompasses multiple diagnostic criteria, gender, reproductive potential and mental health.
URI
https://doi.org/10.1371/journal.pgen.1007813
http://hdl.handle.net/10062/63432
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