Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive age women, yet its etiology is poorly understood. The disorder is defined by its cardinal features: irregular menstrual cycles, hyperandrogenism and a polycystic ovary pattern on ultrasound. In addition, women with PCOS have increased risk for infertility, endometrial cancer, type 2 diabetes and cardiovascular risk factors. We completed a genome-wide association study in collaboration with deCODE in Iceland. The study identified a variant on chromosome 4 reaching genomewide significance in an Icelandic case control cohort and replicating in an identically phenotyped Boston cohort. The broad goal of this proposal is to identify the causal variant that this risk variant marks through fine mapping. We will also examine the functional effects of the causal variant using expression studies and/or assays of protein function. Finally, we will examine the phenotypic features defined by the genotype.
Specific Aim 1 will examine the region around the chromosome 4 variant to identify the causal variant that affects protein production or gene expression. Fine mapping will be performed using common single nucleotide polymorphisms (SNPs) in the HapMap and 1000 genomes projects. In addition, the exons and promoter regions of genes in linkage disequilibrium with the associated variant will be sequenced in large numbers to identify rare variants that may affect protein production or gene expression.
Specific Aim 2 will dissect the phenotype conferred by the genotype in PCOS, controls, males and postmenopausal women using an extensive database assembled by the PI over the past 6 years.
Specific Aim 3 will examine expression of two candidate genes in LD with the chromosome 4 variant in carriers and non-carriers to determine the gene of interest. When a causal variant is identified, expression will also be examined to identify a functional effect of variant(s) in a lymphoblastoid cell line database and in adipose, theca and peripheral white blood cells in vitro using quantitative PCR. Coding sequence causal variants and rare variants will be assessed using signaling assays and overexpression or knock-down of the variants in cell systems and animal models. These studies will uncover the causal variant and gene that is marked by the first known variant identified in a genome-wide case control association study of PCOS. The proposal has the potential to illuminate the etiology of PCOS. Such information has been long in coming and is essential to provide better diagnostic and treatment information for this very common disorder with its adverse health consequences.

Public Health Relevance

Polycystic ovary syndrome is a disorder of irregular menses and elevated androgens that carries a high risk for diabetes, hypertension and elevated lipids. We have now discovered a genetic variant that is associated with polycystic ovary syndrome in a genome-wide association study and will try to determine the causal variant and gene it marks. Discovering the variants and/or gene(s) that predispose to PCOS will determine an etiology and will provide a novel target to develop new treatments for the 1 in 10 reproductive age women it affects.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
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Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
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Taymans, Susan
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Massachusetts General Hospital
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Kim, Hyun-Jun; Adams, Judith M; Gudmundsson, Jens A et al. (2017) Polycystic ovary morphology: age-based ultrasound criteria. Fertil Steril 108:548-553
Bjonnes, Andrew C; Saxena, Richa; Welt, Corrine K (2016) Relationship between polycystic ovary syndrome and ancestry in European Americans. Fertil Steril 106:1772-1777
Day, Felix R; Hinds, David A; Tung, Joyce Y et al. (2015) Causal mechanisms and balancing selection inferred from genetic associations with polycystic ovary syndrome. Nat Commun 6:8464
Hayes, M Geoffrey; Urbanek, Margrit; Ehrmann, David A et al. (2015) Genome-wide association of polycystic ovary syndrome implicates alterations in gonadotropin secretion in European ancestry populations. Nat Commun 6:7502
Castro, Victor; Shen, Yuanyuan; Yu, Sheng et al. (2015) Identification of subjects with polycystic ovary syndrome using electronic health records. Reprod Biol Endocrinol 13:116
Saxena, R; Bjonnes, A C; Georgopoulos, N A et al. (2015) Gene variants associated with age at menopause are also associated with polycystic ovary syndrome, gonadotrophins and ovarian volume. Hum Reprod 30:1697-703
Saxena, R; Georgopoulos, N A; Braaten, T J et al. (2015) Han Chinese polycystic ovary syndrome risk variants in women of European ancestry: relationship to FSH levels and glucose tolerance. Hum Reprod 30:1454-9
Keefe, Candace C; Goldman, Mildred M; Zhang, Ke et al. (2014) Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. PLoS One 9:e93805
Welt, Corrine K; Duran, Jessica M (2014) Genetics of polycystic ovary syndrome. Semin Reprod Med 32:177-82
Hoeger, Kathleen M; Legro, Richard S; Welt, Corrine K (2014) A patient's guide: polycystic ovary syndrome (PCOS). J Clin Endocrinol Metab 99:35A-36A

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