Phenotype and Tissue Expression as a Function of Genetic Risk in Polycystic Ovary Syndrome

<div><p>Genome-wide association studies and replication analyses have identified (n = 5) or replicated (n = 10) DNA variants associated with risk for polycystic ovary syndrome (PCOS) in European women. However, the causal gene and underlying mechanism for PCOS risk at these loci have not been determined. We hypothesized that analysis of phenotype, gene expression and metformin response as a function of genotype would identify candidate genes and pathways that could provide insight into the underlying mechanism for risk at these loci. To test the hypothesis, subjects with PCOS (n = 427) diagnosed according to the NIH criteria (< 9 menses per year and clinical or biochemical hyperandrogenism) and controls (n = 407) with extensive phenotyping were studied. A subset of subjects (n = 38) underwent a subcutaneous adipose tissue biopsy for RNA sequencing and were subsequently treated with metformin for 12 weeks with standardized outcomes measured. Data were analyzed according to genotype at PCOS risk loci and adjusted for the false discovery rate. A gene variant in the <i>THADA</i> locus was associated with response to metformin and metformin was a predicted upstream regulator at the same locus. Genotype at the <i>FSHB</i> locus was associated with LH levels. Genes near the PCOS risk loci demonstrated differences in expression as a function of genotype in adipose including <i>BLK</i> and <i>NEIL2</i> (<i>GATA4</i> locus), <i>GLIPR1</i> and <i>PHLDA1 (KRR1</i> locus). Based on the phenotypes, expression quantitative trait loci (eQTL), and upstream regulatory and pathway analyses we hypothesize that there are PCOS subtypes. <i>FSHB</i>, <i>FHSR</i> and <i>LHR</i> loci may influence PCOS risk based on their relationship to gonadotropin levels. The <i>THADA</i>, <i>GATA4</i>, <i>ERBB4</i>, <i>SUMO1P1</i>, <i>KRR1</i> and <i>RAB5B</i> loci appear to confer risk through metabolic mechanisms. The <i>IRF1</i>, <i>SUMO1P1</i> and <i>KRR1</i> loci may confer PCOS risk in development. The <i>TOX3</i> and <i>GATA4</i> loci appear to be involved in inflammation and its consequences. The data suggest potential PCOS subtypes and point to the need for additional studies to replicate these findings and identify personalized diagnosis and treatment options for PCOS.</p>