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

Felix Day; Tugce Karaderi; Michelle R. Jones; Cindy Meun; Chunyan He; Alex Drong; Peter Kraft; Nan Lin; Hongyan Huang; Linda Broer; Reedik Magi; Richa Saxena; Triin Laisk; Margrit Urbanek; M. Geoffrey Hayes; Gudmar Thorleifsson; Juan Fernandez-Tajes; Anubha Mahajan; Benjamin H. Mullin; Bronwyn G.A. Stuckey; Timothy D. Spector; Scott G. Wilson; Mark O. Goodarzi; Lea Davis; Barbara Obermayer-Pietsch; André G. Uitterlinden; Verneri Anttila; Benjamin M. Neale; Marjo Riitta Jarvelin; Bart Fauser; Irina Kowalska; Jenny A. Visser; Marianne Andersen; Ken Ong; Elisabet Stener-Victorin; David Ehrmann; Richard S. Legro; Andres Salumets; Mark I. McCarthy; Laure Morin-Papunen; Unnur Thorsteinsdottir; Kari Stefansson; Unnur Styrkarsdottir; John R.B. Perry; Andrea Dunaif; Joop Laven; Steve Franks; Cecilia M. Lindgren; Corrine K. Welt; the 23andMe Research Team

doi:10.1371/journal.pgen.1007813

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

Felix Day, Tugce Karaderi, Michelle R. Jones, Cindy Meun, Chunyan He, Alex Drong, Peter Kraft, Nan Lin, Hongyan Huang, Linda Broer, Reedik Magi, Richa Saxena, Triin Laisk, Margrit Urbanek, M. Geoffrey Hayes, Gudmar Thorleifsson, Juan Fernandez-Tajes, Anubha Mahajan, Benjamin H. Mullin, Bronwyn G.A. StuckeyTimothy D. Spector, Scott G. Wilson, Mark O. Goodarzi, Lea Davis, Barbara Obermayer-Pietsch, André G. Uitterlinden, Verneri Anttila, Benjamin M. Neale, Marjo Riitta Jarvelin, Bart Fauser, Irina Kowalska, Jenny A. Visser, Marianne Andersen, Ken Ong, Elisabet Stener-Victorin, David Ehrmann, Richard S. Legro, Andres Salumets, Mark I. McCarthy, Laure Morin-Papunen, Unnur Thorsteinsdottir, Kari Stefansson, Unnur Styrkarsdottir, John R.B. Perry, Andrea Dunaif, Joop Laven, Steve Franks, Cecilia M. Lindgren^*, Corrine K. Welt, the 23andMe Research Team

^*Corresponding author for this work

88 Citations (Scopus)

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.

Original language	English
Article number	e1007813
Journal	PLOS Genetics
Volume	14
Issue number	12
Number of pages	20
ISSN	1553-7390
DOIs	https://doi.org/10.1371/journal.pgen.1007813
Publication status	Published - 2018
Externally published	Yes

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Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteriaFinal published version, 1.46 MBLicence: CC BY

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Day, F., Karaderi, T., Jones, M. R., Meun, C., He, C., Drong, A., Kraft, P., Lin, N., Huang, H., Broer, L., Magi, R., Saxena, R., Laisk, T., Urbanek, M., Hayes, M. G., Thorleifsson, G., Fernandez-Tajes, J., Mahajan, A., Mullin, B. H., ... the 23andMe Research Team (2018). Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. PLOS Genetics, 14(12), Article e1007813. https://doi.org/10.1371/journal.pgen.1007813

Day, F, Karaderi, T, Jones, MR, Meun, C, He, C, Drong, A, Kraft, P, Lin, N, Huang, H, Broer, L, Magi, R, Saxena, R, Laisk, T, Urbanek, M, Hayes, MG, Thorleifsson, G, Fernandez-Tajes, J, Mahajan, A, Mullin, BH, Stuckey, BGA, Spector, TD, Wilson, SG, Goodarzi, MO, Davis, L, Obermayer-Pietsch, B, Uitterlinden, AG, Anttila, V, Neale, BM, Jarvelin, MR, Fauser, B, Kowalska, I, Visser, JA, Andersen, M, Ong, K, Stener-Victorin, E, Ehrmann, D, Legro, RS, Salumets, A, McCarthy, MI, Morin-Papunen, L, Thorsteinsdottir, U, Stefansson, K, Styrkarsdottir, U, Perry, JRB, Dunaif, A, Laven, J, Franks, S, Lindgren, CM, Welt, CK & the 23andMe Research Team 2018, 'Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria', PLOS Genetics, vol. 14, no. 12, e1007813. https://doi.org/10.1371/journal.pgen.1007813

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

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.",

author = "Felix Day and Tugce Karaderi and Jones, {Michelle R.} and Cindy Meun and Chunyan He and Alex Drong and Peter Kraft and Nan Lin and Hongyan Huang and Linda Broer and Reedik Magi and Richa Saxena and Triin Laisk and Margrit Urbanek and Hayes, {M. Geoffrey} and Gudmar Thorleifsson and Juan Fernandez-Tajes and Anubha Mahajan and Mullin, {Benjamin H.} and Stuckey, {Bronwyn G.A.} and Spector, {Timothy D.} and Wilson, {Scott G.} and Goodarzi, {Mark O.} and Lea Davis and Barbara Obermayer-Pietsch and Uitterlinden, {Andr{\'e} G.} and Verneri Anttila and Neale, {Benjamin M.} and Jarvelin, {Marjo Riitta} and Bart Fauser and Irina Kowalska and Visser, {Jenny A.} and Marianne Andersen and Ken Ong and Elisabet Stener-Victorin and David Ehrmann and Legro, {Richard S.} and Andres Salumets and McCarthy, {Mark I.} and Laure Morin-Papunen and Unnur Thorsteinsdottir and Kari Stefansson and Unnur Styrkarsdottir and Perry, {John R.B.} and Andrea Dunaif and Joop Laven and Steve Franks and Lindgren, {Cecilia M.} and Welt, {Corrine K.} and {the 23andMe Research Team}",

year = "2018",

doi = "10.1371/journal.pgen.1007813",

language = "English",

volume = "14",

journal = "PLOS Genetics",

issn = "1553-7390",

publisher = "Public Library of Science",

number = "12",

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TY - JOUR

T1 - Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria

AU - Day, Felix

AU - Karaderi, Tugce

AU - Jones, Michelle R.

AU - Meun, Cindy

AU - He, Chunyan

AU - Drong, Alex

AU - Kraft, Peter

AU - Lin, Nan

AU - Huang, Hongyan

AU - Broer, Linda

AU - Magi, Reedik

AU - Saxena, Richa

AU - Laisk, Triin

AU - Urbanek, Margrit

AU - Hayes, M. Geoffrey

AU - Thorleifsson, Gudmar

AU - Fernandez-Tajes, Juan

AU - Mahajan, Anubha

AU - Mullin, Benjamin H.

AU - Stuckey, Bronwyn G.A.

AU - Spector, Timothy D.

AU - Wilson, Scott G.

AU - Goodarzi, Mark O.

AU - Davis, Lea

AU - Obermayer-Pietsch, Barbara

AU - Uitterlinden, André G.

AU - Anttila, Verneri

AU - Neale, Benjamin M.

AU - Jarvelin, Marjo Riitta

AU - Fauser, Bart

AU - Kowalska, Irina

AU - Visser, Jenny A.

AU - Andersen, Marianne

AU - Ong, Ken

AU - Stener-Victorin, Elisabet

AU - Ehrmann, David

AU - Legro, Richard S.

AU - Salumets, Andres

AU - McCarthy, Mark I.

AU - Morin-Papunen, Laure

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Styrkarsdottir, Unnur

AU - Perry, John R.B.

AU - Dunaif, Andrea

AU - Laven, Joop

AU - Franks, Steve

AU - Lindgren, Cecilia M.

AU - Welt, Corrine K.

AU - the 23andMe Research Team

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

U2 - 10.1371/journal.pgen.1007813

DO - 10.1371/journal.pgen.1007813

M3 - Journal article

C2 - 30566500

AN - SCOPUS:85058879359

SN - 1553-7390

VL - 14

JO - PLOS Genetics

JF - PLOS Genetics

IS - 12

M1 - e1007813

ER -

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

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