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 LHCGR, FSHR, ZNF217, YAP1, INSR, RAB5B, and C9orf3. 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.

Keywords: GWAS; PCOS; genomics; hyperandrogenism; signaling; theca.

Figure 1. Hypothetical model of a GWAS Signaling Cascades involved in PCOS

The schematic shows a putative network of genes postulated to contribute to the hyperandrogenimia associated with PCOS, based on the loci identified in published GWAS and replication studies (GWAS candidates are labeled in rust). The GWAS loci associated with PCOS include: 1) plasma membrane receptors (LHCGR, FSHR INSR); 2) proteins associated with protein trafficking, endocytotic processes, and receptor recycling (DENND1A, RAB5B); and 3) transcription factors (ZNF217, YAP1, TOX3, HMG). The LH/hCG receptor, FSH-receptor, and insulin receptor are all plasma membrane receptors, which are internalized/recycled by clathrin coated pits [20]. DENND1A encodes the plasma membrane protein connecdenn 1, which is involved in clathrin-binding, endocytic processes and receptor recycling [65, 74, 86]. Ras related protein 5B (RAB5B) is a Rab-GTPase, and is also involved in membrane trafficking, endocytosis and receptor recycling [87, 88]. Yes-associated protein (YAP1), transcriptional coactivator of the p300/CBP-mediated transcription complex (TOX3), high mobility group AT-hook 2 (HMGA2), and zinc finger protein 217 (ZNF217) have all be shown to be involved in transcriptional activation/repression [–77, 89]. Abbreviations: PCOS, polycystic ovary syndrome; GWAS, Genome Wide Association Study; DENND1A, connecdenn 1; DENND1A.V2, DENND1A variant 2; LHCGR, LH/CG receptor; YAP1, Yes-associated protein; TOX3, transcriptional coactivator of the p300/CBP-mediated transcription complex; HMGA2, high mobility group AT-hook 2; ZNF217, zinc finger protein 217; RAB5B, ras related protein 5B; INSR, insulin receptor; CYP17A1, cytochrome P450 17α-hydroxylase CYP11A1, cytochrome P450 cholesterol side chain cleavage.