Functional genomics of PCOS: from GWAS to molecular mechanisms

Abstract

Polycystic ovary syndrome (PCOS) is a common endocrinopathy characterized by increased ovarian androgen biosynthesis, anovulation, and infertility. PCOS has a strong heritable component based on familial clustering and twin studies. Genome-wide association studies (GWAS) identified several PCOS candidate loci including, DENND1A, LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3. Here, we review the functional roles of strong PCOS candidate loci focusing on FSHR, LHCGR, INSR and DENND1A. We propose that these candidates comprise a hierarchical signaling network by which DENND1A, LHCGR, INSR, RAB5B, adapter proteins, and associated downstream signaling cascades converge to regulate theca cell androgen biosynthesis. Future elucidation of the functional gene networks predicted by the PCOS GWAS will result in new diagnostic and therapeutic approaches for women with PCOS.

Hormon anty-müllerowski i zespół policystycznych jajników

“…According to Rotterdam criteria, there are four phenotypes of PCOS: I classic phenotype with all three criteria fulfilled, II phenotype with HA and OM, III phenotype with HA and PCOM, and IV phenotype with OM and PCOM [34]. The pathogenesis of the disease is multifactorial, combining genetic predispositions with environmental influence [35]. Women with PCOS are considered as a group with high risk of obesity, insulin resistance, metabolic syndrome, type 2 diabetes, fertility disorders, and cardiovascular diseases [1,36].…”

“…Według kryteriów rotterdamskich wyróżnia się cztery fenotypy PCOS -I fenotyp klasyczny spełniający wszystkie trzy kryteria, II fenotyp -z HA i OM, III fenotyp -z HA i PCOM, IV fenotyp -z OM i PCOM [34]. W patogenezie zespołu odgrywa rolę wiele czynników zarówno genetycznych, jak i środowiskowych [35]. Kobiety z PCOS stanowią grupę zwiększonego ryzyka otyłości, insulinooporności, zespołu metabolicznego, cukrzycy typu 2, niepłodności, chorób układu sercowo--naczyniowego [1,36].…”

Genetic Predisposition to Polycystic Ovary Syndrome, Postpartum Weight Reduction, and Glycemic Changes: A Longitudinal Study in Women With Prior Gestational Diabetes

“…Notably, the DENND1A variant (rs10986105) has been identified as the strongest association in women of European ancestry (27), and the second strongest risk variant associated with PCOS in Han Chinese women (9). The DENND1A gene encodes DENN/MADD domain-containing 1A (DENND1A), which is highly expressed in ovarian theca cells and the adrenal zona reticularis, both androgen-producing tissues (28). Interestingly, quantitative trait analyses have linked the DENND1A locus with glucose and insulin levels, as well as body weight in hu- mans.…”

Cardiometabolic Risks in Polycystic Ovary Syndrome: Non-Traditional Risk Factors and the Impact of Obesity

“…Several loci were identified in these and additional studies in populations of non-Asian descent [19,20] containing genes associated with PCOS, including THADA (thyroid adenoma gene) and DENND1A (involved in the production of endoplasmic reticulum aminopeptidase 1 used for membrane trafficking). Given the overexpression of a DENND1A isoform (variant 2) in PCOS theca cells [21] , this gene may act in concert with genetic variants of gonadotropin or insulin receptors to modulate signal transduction pathways that promote thecal androgen synthesis [22] , leading to metabolic, reproductive, and psychological outcomes in PCOS. At present however, GWAS are a promising but preliminary area of genetic research in PCOS.…”