P353 - ECE_3559 - Genetic variation in the gonadotropin signaling pathway and its role in PCOS pathogenesis

Abstract

Polycystic ovary syndrome (PCOS) is a common, complex endocrinopathy affecting 6-20% of reproductive age women. It is defined by elevated androgens, irregular or absent periods, and polycystic ovarian morphology. Physiological conditions contributing to PCOS pathogenesis include insulin resistance, and ovulatory and gonadotropin signaling dysfunction. Twin and family studies have shown PCOS to be highly heritable, and genome-wide association studies (GWAS) implicate several PCOS susceptibility loci near genes involved in gonadotropin and hypothalamic-pituitary secretion. The gonadotropin hormones, follicle stimulating hormone (FSH) and luteinizing hormone (LH), are neuroendocrine hormones that direct follicle development and overall ovarian health. Reproductive neuroendocrine dysfunction is a major pathophysiological component of PCOS. Women with PCOS have elevated LH levels contributing to hyperandrogenism and oligo/anovulation— two cardinal characteristics of PCOS. Determine the impact of pathogenic variants in the gonadotropin signaling pathway on PCOS pathogenesis and elucidate the molecular mechanisms of impaired gonadotropin signaling. To determine how disease-causing gonadotropin signaling variants contribute to PCOS pathogenesis, we sequenced the gonadotropin genes FSHR, FSHB, LHCGR, and LHB in two independent cohorts of women with PCOS. To elucidate the molecular mechanisms of gonadotropin signaling dysfunction, we used a cAMP assay to screen FSHR variants for impaired function. We found significant and reproducible evidence for association between variants in FSHR and LHCGR and PCOS (P < 1e-15) in two independent cohorts. We found that variation in FSHB is significantly associated with PCOS in our discovery cohort (P < 1e-5) and nominally associated in our replication cohort (P = .02). We identified 27 potentially pathogenic variants (PPVs) across the four gonadotropin genes in two independent cohorts. FSHR variants have been identified in reproductive disorders such as hypogonadotropic hypogonadism (HH) or primary ovarian insufficiency (POI), but no pathogenic FSHR variants have identified in PCOS. We identified 26 PPVs in FSHR in two independent cohorts of women with PCOS. These studies demonstrate that rare variation in the gonadotropin signaling pathway is significantly enriched in PCOS, providing substantial evidence for their role in PCOS pathogenesis. Identifying and understanding genetic contributions to complex endocrinopathies like PCOS can increase our ability to find causal variants and improve treatment efficacy.