The effect of gonadotropin pathway genetic variation on PCOS pathogenesis

PROJECT SUMMARY Polycystic ovary syndrome (PCOS) is a common, complex, and heritable endocrinopathy, affecting 6-20% of reproductive age women. PCOS is defined by elevated androgens, irregular or absent periods, and polycystic ovarian morphology and is diagnosed by the presence of two or more of these reproductive phenotypes. There are many interacting physiological pathways that contribute to PCOS pathogenesis, including insulin resistance, ovulatory dysfunction, and gonadotropin signaling dysfunction. Due to the multifactorial nature of this disorder, current clinical interventions are variably effective and do not address the underlying causes of PCOS. Twin and family studies have shown PCOS to be highly heritable. Furthermore, genome-wide association studies (GWAS) have implicated genes involved in insulin resistance, diabetes, ovulation, and gonadotropin signaling. Genetic factors, therefore, are likely contribute to the heterogeneity of PCOS. With the advent of Next Generation Sequencing (NGS) it is now feasible to comprehensively identify genetic variation mapping to a genome, gene, or molecular pathway. Our long-term objective is to identify genetic drivers of PCOS. The gonadotropin hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are part of the neuroendocrine signaling network that direct follicle development and overall ovarian health. Reproductive neuroendocrine dysfunction is a major pathophysiological component of PCOS. Women with PCOS have an imbalance of LH:FSH ratio resulting in hyperandrogenism and oligo/anovulation—two cardinal characteristics of PCOS. Although gonadotropin genes have long been implicated in PCOS pathogenesis, no causal variants have yet been identified. Given the physiological relevance of gonadotropin signaling dysfunction and genetic implications of gonadotropin genes in PCOS, our hypothesis is that genetic variation in gonadotropin genes contributes to PCOS pathogenesis. Therefore, our goal is to elucidate the molecular mechanisms of gonadotropin signaling dysfunction in PCOS. In this study, we will evaluate the genetic burden of potentially pathogenic variants (PPVs) in the gonadotropin signaling pathway in women with PCOS using two independent PCOS cohorts (Aim 1). Furthermore, we will elucidate the molecular mechanisms by which these pathogenic variants cause gonadotropin signaling dysfunction through functional studies (Aim 2). Successful implementation of these aims will reveal the extent to which gonadotropin dysfunction is an underlying cause of PCOS, which members of the gonadotropin signaling pathway are impaired in PCOS, and how pathogenic variants in this pathway impair gonadotropin signaling at the cellular level.