. 2015 Aug 18:6:7502.

doi: 10.1038/ncomms8502.

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

M Geoffrey Hayes¹, Margrit Urbanek², David A Ehrmann³, Loren L Armstrong⁴, Ji Young Lee⁴, Ryan Sisk⁴, Tugce Karaderi⁵, Thomas M Barber⁶, Mark I McCarthy⁷, Stephen Franks⁸, Cecilia M Lindgren⁹, Corrine K Welt¹⁰, Evanthia Diamanti-Kandarakis¹¹, Dimitrios Panidis¹², Mark O Goodarzi¹³, Ricardo Azziz¹⁴, Yi Zhang¹⁵, Roland G James¹⁵, Michael Olivier¹⁶, Ahmed H Kissebah¹⁵; Reproductive Medicine Network; Elisabet Stener-Victorin³⁹, Richard S Legro⁴⁰, Andrea Dunaif²

Collaborators, Affiliations

Collaborators

Reproductive Medicine Network:
Ruben Alvero¹⁷, Huiman X Barnhart¹⁸, Valerie Baker¹⁹, Kurt T Barnhart²⁰, G Wright Bates²¹, Robert G Brzyski²², Bruce R Carr²³, Sandra A Carson²⁴, Peter Casson²⁵, Nicholas A Cataldo¹⁹, Gregory Christman²⁶, Christos Coutifaris²⁰, Michael P Diamond²⁷, Esther Eisenberg²⁸, Gabriella G Gosman²⁹, Linda C Giudice³⁰, Daniel J Haisenleder³¹, Hao Huang³², Stephen A Krawetz²⁷, Scott Lucidi³³, Peter G McGovern³⁴, Evan R Myers³⁵, John E Nestler³⁶, Dana Ohl²⁶, Nanette Santoro¹⁷, William D Schlaff¹⁷, Peter Snyder²⁰, Michael P Steinkampf²¹, J C Trussell³⁷, Rebecca Usadi³⁸, Qingshang Yan³², Heping Zhang³²

Affiliations

¹ 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [3] Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.
² 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
³ Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA.
⁴ Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁶ Warwick Medical School, University of Warwick, Warwick CV4 7AL, UK.
⁷ 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK [3] Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington OX3 7LE, UK.
⁸ Institute of Reproductive &Developmental Biology, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
⁹ 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
¹⁰ Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA.
¹¹ Endocrinology and Metabolism, University of Athens Medical School, Athens 115 27, Greece.
¹² Division of Endocrinology and Human Reproduction, 2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki 54124, Greece.
¹³ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
¹⁴ Departments of Obstetrics and Gynecology and Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
¹⁵ 1] TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA [2] Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
¹⁶ Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78256, USA.
¹⁷ Department of Obstetrics and Gynecology, University of Colorado, Aurora, Colorado 80045, USA.
¹⁸ Department of Biostatistics &Bioinformatics, Duke University Medical Centre, Durham, North Carolina 27710, USA.
¹⁹ Department of Obstetrics and Gynecology, Stanford University Medical Centre, Stanford, California 94304, USA.
²⁰ Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
²¹ Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35249, USA.
²² Department of Obstetrics and Gynecology, University of Texas Health Science Centre, San Antonio, Texas 78229, USA.
²³ Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
²⁴ Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA.
²⁵ Department of Obstetrics and Gynecology, University of Vermont, Burlington, Vermont 05495, USA.
²⁶ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109, USA.
²⁷ Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
²⁸ Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland 20852, USA.
²⁹ Department of Obstetrics Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
³⁰ Department of Obstetrics Gynecology, and Reproductive Sciences, University of California at San Francisco, San Francisco, California 94143, USA.
³¹ Ligand Core Laboratory, University of Virginia Center for Research in Reproduction, Charlottesville, Virginia 22908, USA.
³² Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut 06520, USA.
³³ Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
³⁴ Department of Obstetrics, Gynecology and Women's Health, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
³⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
³⁶ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
³⁷ Department of Urology, State University of New York Upstate Medical University, Onondaga, New York 13210, USA.
³⁸ Carolinas Medical Center, Charlotte, North Carolina 28204, USA.
³⁹ Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
⁴⁰ Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.

PMID: 26284813
PMCID: PMC4557132
DOI: 10.1038/ncomms8502

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

M Geoffrey Hayes et al. Nat Commun. 2015.

. 2015 Aug 18:6:7502.

doi: 10.1038/ncomms8502.

Authors

Collaborators

Reproductive Medicine Network:
Ruben Alvero¹⁷, Huiman X Barnhart¹⁸, Valerie Baker¹⁹, Kurt T Barnhart²⁰, G Wright Bates²¹, Robert G Brzyski²², Bruce R Carr²³, Sandra A Carson²⁴, Peter Casson²⁵, Nicholas A Cataldo¹⁹, Gregory Christman²⁶, Christos Coutifaris²⁰, Michael P Diamond²⁷, Esther Eisenberg²⁸, Gabriella G Gosman²⁹, Linda C Giudice³⁰, Daniel J Haisenleder³¹, Hao Huang³², Stephen A Krawetz²⁷, Scott Lucidi³³, Peter G McGovern³⁴, Evan R Myers³⁵, John E Nestler³⁶, Dana Ohl²⁶, Nanette Santoro¹⁷, William D Schlaff¹⁷, Peter Snyder²⁰, Michael P Steinkampf²¹, J C Trussell³⁷, Rebecca Usadi³⁸, Qingshang Yan³², Heping Zhang³²

Affiliations

¹ 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [3] Department of Anthropology, Northwestern University, Evanston, Illinois 60208, USA.
² 1] Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA [2] Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
³ Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA.
⁴ Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
⁵ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
⁶ Warwick Medical School, University of Warwick, Warwick CV4 7AL, UK.
⁷ 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK [3] Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington OX3 7LE, UK.
⁸ Institute of Reproductive &Developmental Biology, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
⁹ 1] Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK [2] Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, Massachusetts 02142, USA.
¹⁰ Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA.
¹¹ Endocrinology and Metabolism, University of Athens Medical School, Athens 115 27, Greece.
¹² Division of Endocrinology and Human Reproduction, 2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki 54124, Greece.
¹³ Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
¹⁴ Departments of Obstetrics and Gynecology and Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
¹⁵ 1] TOPS Obesity and Metabolic Research Center, Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA [2] Human and Molecular Genetics Center, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
¹⁶ Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78256, USA.
¹⁷ Department of Obstetrics and Gynecology, University of Colorado, Aurora, Colorado 80045, USA.
¹⁸ Department of Biostatistics &Bioinformatics, Duke University Medical Centre, Durham, North Carolina 27710, USA.
¹⁹ Department of Obstetrics and Gynecology, Stanford University Medical Centre, Stanford, California 94304, USA.
²⁰ Department of Obstetrics and Gynecology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, USA.
²¹ Department of Obstetrics and Gynecology, University of Alabama, Birmingham, Alabama 35249, USA.
²² Department of Obstetrics and Gynecology, University of Texas Health Science Centre, San Antonio, Texas 78229, USA.
²³ Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
²⁴ Department of Obstetrics and Gynecology, Baylor College of Medicine, Houston, Texas 77030, USA.
²⁵ Department of Obstetrics and Gynecology, University of Vermont, Burlington, Vermont 05495, USA.
²⁶ Department of Obstetrics and Gynecology, University of Michigan, Ann Arbor, Michigan 48109, USA.
²⁷ Department of Obstetrics and Gynecology, Wayne State University, Detroit, Michigan 48201, USA.
²⁸ Fertility and Infertility Branch, Eunice Kennedy Shriver National Institute of Child Health and Human Development, Rockville, Maryland 20852, USA.
²⁹ Department of Obstetrics Gynecology, and Reproductive Sciences, University of Pittsburgh, Pittsburgh, Pennsylvania 15213, USA.
³⁰ Department of Obstetrics Gynecology, and Reproductive Sciences, University of California at San Francisco, San Francisco, California 94143, USA.
³¹ Ligand Core Laboratory, University of Virginia Center for Research in Reproduction, Charlottesville, Virginia 22908, USA.
³² Department of Biostatistics, Yale University School of Public Health, New Haven, Connecticut 06520, USA.
³³ Department of Obstetrics and Gynecology, Virginia Commonwealth University, Richmond, Virginia 23298, USA.
³⁴ Department of Obstetrics, Gynecology and Women's Health, University of Medicine and Dentistry of New Jersey, Newark, New Jersey 07103, USA.
³⁵ Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina 27710, USA.
³⁶ Department of Internal Medicine, Virginia Commonwealth University School of Medicine, Richmond, Virginia 23298, USA.
³⁷ Department of Urology, State University of New York Upstate Medical University, Onondaga, New York 13210, USA.
³⁸ Carolinas Medical Center, Charlotte, North Carolina 28204, USA.
³⁹ Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
⁴⁰ Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.

PMID: 26284813
PMCID: PMC4557132
DOI: 10.1038/ncomms8502

Erratum in

Corrigendum: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.
Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, Karaderi T, Barber TM, McCarthy MI, Franks S, Lindgren CM, Welt CK, Diamanti-Kandarakis E, Panidis D, Goodarzi MO, Azziz R, Zhang Y, James RG, Olivier M, Kissebah AH; Reproductive Medicine Network; Stener-Victorin E, Legro RS, Dunaif A. Hayes MG, et al. Nat Commun. 2016 Feb 12;7:10762. doi: 10.1038/ncomms10762. Nat Commun. 2016. PMID: 26867975 Free PMC article. No abstract available.
Publisher Correction: Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.
Hayes MG, Urbanek M, Ehrmann DA, Armstrong LL, Lee JY, Sisk R, Karaderi T, Barber TM, McCarthy MI, Franks S, Lindgren CM, Welt CK, Diamanti-Kandarakis E, Panidis D, Goodarzi MO, Azziz R, Zhang Y, James RG, Olivier M, Kissebah AH; Reproductive Medicine Network; Stener-Victorin E, Legro RS, Dunaif A. Hayes MG, et al. Nat Commun. 2020 Apr 28;11(1):2158. doi: 10.1038/s41467-020-15793-w. Nat Commun. 2020. PMID: 32345980 Free PMC article.

Abstract

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS. Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels. Three loci reach genome-wide significance in the case-control meta-analysis, two novel loci mapping to chr 8p23.1 [Corrected] and chr 11p14.1, and a chr 9q22.32 locus previously found in Chinese PCOS. The same chr 11p14.1 SNP, rs11031006, in the region of the follicle-stimulating hormone B polypeptide (FSHB) gene strongly associates with PCOS diagnosis and luteinizing hormone levels. These findings implicate neuroendocrine changes in disease pathogenesis.

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Figures

**Figure 1. Genome-wide association results for traits with genomewide significant hits in the meta-analysis of GWAS and replication phases.**
Manhattan plots for a. PCOS, b. LH levels. Alternating blue and red colours indicate genotyped SNPs, and accompanying black and grey colours indicate imputed variants, on odd and even chromosomes, respectively. The red horizontal red line indicates genomewide significance. QQ plots and λ_GC/ λ_GC1000 are inset in the upper right corner of each plot. For (a) PCOS, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (b) LH levels, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).

**Figure 2. Locuszoom plot of association results, linkage disequilibrium and recombination rates around the genome-wide significant loci.**
(a) Chr. 9 PCOS locus (*c9orf3/FANCC*), (b) Chr. 11 PCOS locus (*FSHB/ARL14EP*), (c) Chr. 8 PCOS locus (*GATA4/NEIL2*), (d) Chr. 11 LH locus (*FSHB/ARL14EP*). In each, the top panel reflects the meta-analysis results of the combined GWAS and replication phases. The LD estimates are colour coded as a heatmap from dark blue (0≥r²>0.2) to red (0.8≥r²>1.0). Recombination hotspots are indicated by the yellow lines (recombination rate in cM Mb^-1 from HapMap (http://hapmap.ncbi.nlm.nih.gov/downloads/recombination/2008-03_rel22_B36/rates/)). The bottom panel shows the genes and their orientation for each region. For (a–c) PCOS loci, P values are from sample-size weighted two-strata meta-analysis of strata-specific logistic regression P values (Stage 1: 984 cases and 2,964 population control women; Stage 2: 1,799 PCOS cases and 1,231 phenotyped reproductively normal control women). For (d) LH level locus, P values are from sample-size weighted two-strata meta-analysis of strata-specific linear regression P values (Stage 1: 645 PCOS cases; Stage 2: 399 PCOS cases).

**Figure 3. ENCODE histone mark profile for genomewide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).**
Methylation marks in four PCOS relevant human tissue mapping to: (a) Chr. 9 PCOS locus (*c9orf3/FANCC*), (b) Chr. 11 PCOS and LH level locus (*FSHB/ARL14EP*) and (c) Chr. 8 PCOS locus (*GATA4/NEIL2*). Each is a schematic of the genomic region including diagrams of genes mapping to the region. ChipSeq signal tracks for each tissue (AN, adipose nuclei; AL, adult liver; PI, pancreatic islets; SM, skeletal muscle) for six histone marks (H3K27m3, H3K36m3, H3K4m1, H3K4m3, H3K9ac and H3K9m3) are labelled to the left of the panel.

**Figure 4. ENCODE mRNA levels for genome-wide significant PCOS and LH level GWAS loci (http://www.roadmapepigenomics.org/data).**
RNAseq levels in four PCOS relevant human tissue mapping to the (a) Chr. 9 PCOS locus (*c9orf3/FANCC*), (b) Chr. 11 PCOS and LH level locus (*FSHB/ARL14EP*) and (c) Chr. 8 PCOS locus (*GATA4/NEIL2*). Each is a schematic of the genomic region including diagrams of genes mapping to the region. Sources of RNA are labelled to the left of the panel.

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References

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1. Franks S., Stark J. & Hardy K. Follicle dynamics and anovulation in polycystic ovary syndrome. Hum. Reprod. Update 14, 367–378 (2008). - PubMed
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Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

Collaborators

Affiliations

Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations

Authors

Collaborators

Affiliations

Erratum in

Abstract

Figures

References

Publication types

MeSH terms

Associated data

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical