Linkage and association of variants in the dopamine receptor 2 gene (DRD2) with polycystic ovary syndrome

Abstract

AbstractPolycystic ovarian syndrome (PCOS) is a disorder with a foundation of neuroendocrine dysfunction, characterized by increased gonadotropin-releasing hormone (GnRH) pulsatility, which is antagonized by dopamine. The dopamine receptor 2 (DRD2), encoded by theDRD2gene, has been shown to mediate dopamine’s inhibition of GnRH neuron excitability through pre- and post-synaptic interactions in murine models. Further, DRD2 is known to mediate prolactin (PRL) inhibition by dopamine, and high blood level of PRL have been found in more than one third of women with PCOS. We recently identifiedPRLas a gene contributing to PCOS risk and reportedDRD2conferring risk for type 2 diabetes and depression, which can both coexist with PCOS. Given DRD2 mediating dopamine’s action on neuroendocrine profiles and association with metabolic-mental states related to PCOS, polymorphisms inDRD2may predispose to development of PCOS. Therefore, we aimed to investigate whetherDRD2variants are in linkage to and/or linkage disequilibrium (i.e., linkage and association) with PCOS in Italian families. In 212 Italian families, we tested 22 variants within theDRD2gene for linkage and linkage disequilibrium with PCOS. We identified five novel variants significantly linked to the risk of PCOS. This is the first study to identifyDRD2as a risk gene in PCOS, however, functional studies are needed to confirm these results.