Colocalization highlights genes in hypothalamic–pituitary–gonadal axis as potentially mediating polycystic ovary syndrome risk

<jats:title>Abstract</jats:title><jats:p>Polycystic ovary syndrome (PCOS) is a common disease in women with consequences for reproductive, metabolic and psychological health. Women with PCOS have disrupted signalling in the hypothalamic-pituitary-gonadal axis and studies have indicated that the disease has a large genetic component. While a recent genome-wide association study of PCOS performed in up to 10,074 cases and 103,164 controls of European decent identified 14 PCOS-associated regions, much of the disease pathophysiology remains unclear.</jats:p><jats:p>Here, we use a Bayesian colocalization approach to highlight genes that may have a potential role in PCOS pathophysiology and thus are of particular interest for further functional follow-up. We evaluated the posterior probabilities of shared causal variants between PCOS genetic risk loci and intermediate cellular phenotypes in one protein and two expression quantitative trait locus datasets, respectively. Sample sizes ranged from 80 to 31,684. In total, we identified seven proteins or genes with evidence of a shared causal variant for almost a third of PCOS signals, including follicle stimulating hormone (FSH) and the genes <jats:italic>ERBB3</jats:italic>, <jats:italic>IKZF4</jats:italic>, <jats:italic>RPS26</jats:italic>, <jats:italic>SUOX</jats:italic>, <jats:italic>ZFP36L2</jats:italic>, and <jats:italic>C8orf49</jats:italic>. Several of these genes and proteins have been implicated in the hypothalamic-pituitary-gonadal signalling pathway.</jats:p><jats:p>In summary, our results suggest potential effector proteins and genes for PCOS association signals. This highlights genes for functional follow-up in order to demonstrate a causal role in PCOS pathophysiology.</jats:p>