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 Andre 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

MRC Epidemiology Unit, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| Department of Biological Sciences, Faculty of Arts and Sciences, Eastern Mediterranean University, Famagusta, Cyprus.| Center for Bioinformatics & Functional Genomics, Department of Biomedical Sciences, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.| Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.| Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.| University of Kentucky Markey Cancer Center, Lexington, Kentucky, United States of America.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.| Department of Internal Medicine, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.| University of Kentucky Markey Cancer Center, Lexington, Kentucky, United States of America.| Departments of Epidemiology and Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America.| Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.| Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.| Broad Institute of Harvard and MIT and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.| Estonian Genome Center, Institute of Genomics, University of Tartu, Tartu, Estonia.| Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.| Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.| Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.| Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.| Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.| Department of Anthropology, Northwestern University, Evanston, Illinois, United States of America.| deCODE genetics/Amgen, Reykjavik, Iceland.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.| Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.| School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.| Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.| School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.| Keogh Institute for Medical Research, Nedlands, Western Australia, Australia.| Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.| Department of Endocrinology & Diabetes, Sir Charles Gairdner Hospital, Nedlands, Western Australia, Australia.| School of Medicine and Pharmacology, University of Western Australia, Crawley, Western Australia, Australia.| Department of Twin Research & Genetic Epidemiology, King's College London, London, United Kingdom.| Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California, United States of America.| Department of Medicine, Division of Genetic Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.| Vanderbilt Genomics Institute, Vanderbilt University Medical Center, Nashville, Tennessee, United States of America.| Division of Endocrinology and Diabetology, Department of Internal Medicine Medical University of Graz, Graz, Austria.| Department of Internal Medicine, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.| Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.| Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.| Stanley Center for Psychiatric Genetics, Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America.| Analytic and Translational Genetics Unit, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.| Department of Epidemiology and Biostatistics, MRC-PHE Centre for Environment and Health, School of Public Health, Imperial College London, London, United Kingdom.| Center for Life Course Health Research, Faculty of Medicine, University of Oulu, Oulu, Finland.| Biocenter Oulu, University of Oulu, Oulu, Finland.| Unit of Primary Care, Oulu University Hospital, Oulu, Finland.| Department of Reproductive Medicine and Gynaecology, University Medical Center, Utrecht, The Netherlands.| Department of Internal Medicine and Metabolic Diseases, Medical University of Bialystok, Bialystok, Poland.| Department of Internal Medicine, Section of Endocrinology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.| Odense University Hospital, University of Southern Denmark, Odense, Denmark.| MRC Epidemiology Unit, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.| Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.| Department of Medicine, Section of Adult and Paediatric Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois, United States of America.| Department of Obstetrics and Gynecology and Public Health Sciences, Penn State University College of Medicine, Hershey, Pennsylvania, United States of America.| Department of Obstetrics and Gynaecology, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.| Competence Centre on Health Technologies, Tartu, Estonia.| Institute of Bio- and Translational Medicine, University of Tartu, Tartu, Estonia.| Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford, United Kingdom.| Oxford NIHR Biomedical Research Centre, Churchill Hospital, Oxford, United Kingdom.| Department of Obstetrics and Gynecology, University of Oulu and Oulu University Hospital, Medical Research Center, PEDEGO Research Unit, Oulu, Finland.| deCODE genetics/Amgen, Reykjavik, Iceland.| Faculty of Medicine, University of Iceland, Reykjavik, Iceland.| deCODE genetics/Amgen, Reykjavik, Iceland.| Faculty of Medicine, University of Iceland, Reykjavik, Iceland.| deCODE genetics/Amgen, Reykjavik, Iceland.| MRC Epidemiology Unit, Cambridge Biomedical Campus, University of Cambridge School of Clinical Medicine, Cambridge, United Kingdom.| Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States of America.| Division of Endocrinology, Diabetes and Bone Disease, Icahn School of Medicine at Mount Sinai, New York, New York, United States of America.| Division of Reproductive Endocrinology and Infertility, Department of Obstetrics and Gynaecology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.| Institute of Reproductive & Developmental Biology, Department of Surgery & Cancer, Imperial College London, London, United Kingdom.| The Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.| Broad Institute of Harvard and MIT and Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.| Big Data Institute, Li Ka Shing Centre for Health Information and Discovery, Nuffield Department of Medicine, University of Oxford, Oxford, United Kingdom.| Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah, United States of America.| Reproductive Endocrine Unit, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

PLoS Genet. 2018 Dec 19;14(12):e1007813. doi: 10.1371/journal.pgen.1007813.

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.

Dunaif Andrea

Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611.

J Clin Endocrinol Metab. 2016 Mar;101(3):759-68. doi: 10.1210/jc.2015-3780. Epub

CONTEXT: Polycystic ovary syndrome (PCOS) is a common complex genetic disease. It is characterized by hyperandrogenism, gonadotropin secretory changes, polycystic ovarian morphology, and insulin resistance. The etiology of PCOS remains unknown, but modern genetic approaches, such as genome-wide association studies (GWAS), Mendelian randomization, and next-generation sequencing, promise to identify the pathways that are primarily disrupted. EVIDENCE ACQUISITION: The literature on PCOS, including the author's research, is discussed. EVIDENCE SYNTHESIS: Recent genetic analyses are reviewed.
CONCLUSIONS: Considerable progress has been made mapping PCOS susceptibility genes. GWAS have implicated gonadotropin secretion and action as important primary defects in disease pathogenesis in European and Han Chinese PCOS cohorts, respectively. European women with the National Institutes of Health and Rotterdam phenotypes as well as those with self-reported PCOS have some gene regions in common, such as chromosome 11p14.1 region containing the FSH B polypeptide (FSHB) gene, suggesting shared genetic susceptibility. Several chromosomal signals are significant in both Han Chinese and European PCOS cohorts, suggesting that the susceptibility genes in these regions are evolutionarily conserved. In addition, GWAS have suggested that DENND1A, epidermal growth factor signaling, and DNA repair pathways play a role in PCOS pathogenesis. Only a small amount of the heritability of PCOS is accounted for by the common susceptibility variants mapped so far. Future studies should clarify the contribution of rare genetic variants and epigenetic factors to the PCOS phenotype. Furthermore, Mendelian randomization can be used to clarify causal relationships, and phenome-wide association studies can provide insight into health risks associated with PCOS susceptibility variants.