Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria
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Large-scale genome-wide meta-analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. / 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, Triin; Urbanek, Margrit; Hayes, M. Geoffrey; 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; Obermayer-Pietsch, Barbara; Uitterlinden, André G.; Anttila, Verneri; Neale, Benjamin M.; Jarvelin, Marjo Riitta; Fauser, Bart; Kowalska, Irina; Visser, Jenny A.; Andersen, Marianne; Ong, Ken; Stener-Victorin, Elisabet; Ehrmann, David; Legro, Richard S.; Salumets, Andres; McCarthy, Mark I.; Morin-Papunen, Laure; Thorsteinsdottir, Unnur; Stefansson, Kari; Styrkarsdottir, Unnur; Perry, John R.B.; Dunaif, Andrea; Laven, Joop; Franks, Steve; Lindgren, Cecilia M.; Welt, Corrine K.; the 23andMe Research Team.
I: PLOS Genetics, Bind 14, Nr. 12, e1007813, 2018.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
N1 - Correction: 10.1371/journal.pgen.1008517
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
VL - 14
JO - P L o S Genetics
JF - P L o S Genetics
SN - 1553-7390
IS - 12
M1 - e1007813
ER -
ID: 226395220