Genetic Sex Effects of Polycystic Ovary Syndrome Reveal Distinct Metabolic Etiology

Females with polycystic ovary syndrome (PCOS) have an increased risk of developing metabolic disorders such as insulin resistance, obesity, and type 2 diabetes (T2D). High-risk groups or individuals with a family history are more likely to have a greater genetic susceptibility to these diseases, which drastically increases their risk of developing other chronic health conditions. In this study, we systematically evaluated the bidirectional genetic burden of PCOS and its comorbidities among females and males. First, we analyzed the pleiotropic effects of the PCOS polygenic risk score (PRS), a measurement of genetic liability to PCOS, across 1,857 medical conditions recorded in the Vanderbilt University Medical Center electronic health record. We conducted a phenome-wide association study (PheWAS) adjusted for median age, sex, and genetic ancestry. In the European sex-combined model (n = 72,824), we observed that PCOS PRS was significantly (Bonferroni corrected p < 7.86e-06) associated with T2D (OR = 1.11, p = 8.75e-08) and hypertension (OR = 1.06, p = 1.13e-07) in addition to polycystic ovaries (OR = 1.11, p = 1.91e-07). In the sex-stratified model, we found that males (n = 32,022) with a higher PRS for PCOS were more likely to develop cardiovascular diseases (CVD) compared to females (n = 40,802) who had higher odds of developing T2D. Although we were underpowered to detect any phenome-wide significant effects in our African descent sample (n=15,283), uterine leiomyoma (OR = 1.24, p = 3.79e-03), osteoarthritis (OR = 1.21, p = 3.94e-03), and benign neoplasm of uterus (OR = 1.24, p = 4.00e-03) were the top three nominal significant results (p < 0.05) in females (n = 9,418). To understand the genetic relationships observed in the PheWAS, we used LD score regression to determine the genetic correlation between the phenotypes. We found that PCOS was positively correlated with T2D (rg = 31%), systolic blood pressure (rg = 12%), and pulse pressure (rg = 15%). However, we found no significant associations between the genetic risk of CVD and PCOS diagnosis in the European or African descent samples. Our findings show that the genetic architecture of PCOS has distinct metabolic sex differences, but the genetic risk of those comorbidities is not predictive of a PCOS diagnosis. This suggests that other drivers are contributing to the endocrine and cardiovascular comorbid signatures that underlie PCOS.