Polycystic ovary syndrome (PCOS) is a highly heritable, common complex disorder. It is a major risk factor for type 2 diabetes in women and the leading cause of anovulatory infertility. Male as well as female first- degree relatives also have metabolic and reproductive phenotypes characteristics of the syndrome thereby substantially amplifying its public health impact. We recently completed two genomewide association studies (GWAS) to identify genetic loci associated with PCOS and its quantitative traits in PCOS women of European (EU) and Han Chinese (HC) ancestry. We mapped common genetic susceptibility loci in women of EU ancestry with PCOS fulfilling criteria for the classic NIH phenotype that confers the highest risk for re- productive and metabolic morbidities. Both PCOS diagnosis and luteinizing hormone (LH) levels were associated variants in or near the gene for follicle stimulating hormone B polypeptide (FSHB) at genomewide significant levels (P<5x10-8). In the HC PCOS GWAS, including cases fulfilling the broader Rotterdam criteria, genomewide significant associations were found with variants in or near the gene for luteinizing hormone/choriogonadotropin receptor (LHCGR) and the receptor for FSH (FSHR). These findings implicate neuroendocrine changes in disease pathogenesis. We also found overlap in association signals that reached genomewide significance in one of the two populations in genomic regions not currently known to be involved with the neuroendocrine system, specifically c9orf3, DENND1A, and THADA, which suggests disruption in additional biologic pathways contribute to PCOS etiology. We will test the hypothesis that low frequency and rare genetic variants found in high linkage disequilibrium with these common variants contribute to the defined associations and that the functional consequence of the causal variants will include altered gene expression in the following Aims. 1) To use targeted genomic capture and next generation sequencing to comprehensively identify low frequency and rare variants within six of the associated loci (c9orf3, DENND1A, THADA, FSHB, LHCGR, FSHR). This will be done using DNA from in a multiethnic cohort of three ancestry groups (EU, HC and African American [AA]) in the highest and lowest counts of risk alleles for PCOS cases and controls, respectively. 2) To functionally characterize putative regulatory variants contributing to PCOS and infer potential impact in tissues of interest (theca and HepG2 cells) to PCOS. 3) To demonstrate that variants with a functional impact are associated with PCOS and associated quantitative traits by genotyping the most highly prioritized SNPs in ? 8,500 additional PCOS cases and controls in the same multiethnic cohort of three ancestry groups (EU, HC, AA). If these aims are achieved, the findings will have a sustained and lasting impact on the field by elucidating the functional consequences of genetic variation in PCOS pathogenesis. These findings could identify novel therapeutic targets and genetic variants conferring substantial risk that could be used for disease prediction.
Polycystic ovary syndrome (PCOS) is one of the most common disorders of reproductive age women worldwide and a leading risk factor for type 2 diabetes mellitus. We are mapping chromosomal regions that have a high likelihood of containing genes causing PCOS. These findings could also identify novel therapeutic targets and genetic variants conferring substantial risk that could be used for PCOS prediction and prevention.