Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations.
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.
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.
M Geoffrey
MG
Hayes
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.
Margrit
M
Urbanek
Section of Endocrinology, Diabetes, and Metabolism, The University of Chicago, Chicago, Illinois 60637, USA.
David A
DA
Ehrmann
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Loren L
LL
Armstrong
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Ji Young
JY
Lee
Division of Endocrinology, Metabolism, and Molecular Medicine, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, Illinois 60611, USA.
Ryan
R
Sisk
Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.
Tugce
T
Karaderi
Warwick Medical School, University of Warwick, Warwick CV4 7AL, UK.
Thomas M
TM
Barber
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.
Mark I
MI
McCarthy
Institute of Reproductive &Developmental Biology, Hammersmith Hospital, Imperial College London, London W12 0NN, UK.
Stephen
S
Franks
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.
Cecilia M
CM
Lindgren
Division of Endocrinology, Metabolism and Diabetes, University of Utah, Salt Lake City, Utah 84112, USA.
Corrine K
CK
Welt
Endocrinology and Metabolism, University of Athens Medical School, Athens 115 27, Greece.
Evanthia
E
Diamanti-Kandarakis
Division of Endocrinology and Human Reproduction, 2nd Department of Obstetrics and Gynecology, Aristotle University of Thessaloniki 54124, Greece.
Dimitrios
D
Panidis
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA.
Mark O
MO
Goodarzi
Departments of Obstetrics and Gynecology and Medicine, Medical College of Georgia, Georgia Regents University, Augusta, Georgia 30912, USA.
Ricardo
R
Azziz
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.
Yi
Y
Zhang
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.
Roland G
RG
James
Department of Genetics, Texas Biomedical Research Institute, San Antonio, Texas 78256, USA.
Michael
M
Olivier
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.
Ahmed H
AH
Kissebah
Department of Physiology and Pharmacology, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
Elisabet
E
Stener-Victorin
Department of Obstetrics and Gynecology, Penn State College of Medicine, Hershey, Pennsylvania 17033, USA.
Richard S
RS
Legro
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.
Andrea
A
Dunaif
D000293:Adolescent; D000328:Adult; D016022:Case-Control Studies; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006801:Humans; D008875:Middle Aged; D011085:Polycystic Ovary Syndrome / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D040641:Quantitative Trait Loci; D044465:White People / Q000235:genetics*; D055815:Young Adult