Polygenic Risk Stratification for Cardiovascular Disease in Young Male Veterans presenting with Erectile Dysfunction

SUMMARY Erectile dysfunction (ED) affects up to 62% of Veterans and represents a common, yet underappreciated component of multi-morbidity. In addition to the negative impact of ED on quality of life, ED is also an independent risk factor for cardiovascular disease and can represent a precipitating condition for a major adverse cardiac event (MACE). The reliable identification of men with ED who should initiate intensive CVD risk reduction therapies represents a key knowledge gap. There is a critical need for ED-specific precision medicine approaches for the prevention of MACE. This proposal uses innovative approaches on big data from the Million Veterans Program (MVP) to better understand causes of ED and improving CVD risk prediction. The overarching hypothesis is that the risk of CVD in men with ED is variable and dependent on the differential, causal contributions from associated cardiometabolic traits and psychiatric conditions. To accomplish the three research aims, we will first start by assessing multimorbidity burden in Veterans with ED in Aim 1. Using clustering analysis of individuals with ED, we will identify multiple subtypes of ED based on multimorbidity burden. These ED disease clusters will be assessed for their differential association with MACE. In Aim 2, we will leverage genome wide association studies (GWAS) to explore causal inference for cardiometabolic and psychiatric traits with ED using population-specific and multi-population Mendelian Randomization approaches. Additionally, we will perform a GWAS for ED within the larger, more ethnically diverse MVP and meta-GWAS with other large genetic datasets to identify additional risk variants for ED and improve the statistical power of our analyses in Aim 2 and Aim 3. Lastly, in Aim 3, we will assess the differential, causal effect of drugs used for cardiometabolic and psychiatric conditions on ED by using drug-MR analyses, leveraging DNA variants for genes encoding these drug targets. Successful completion of this VA Career Development Award-2 (CDA-2) will enable the candidate to become a VA surgeon-scientist and establish an independent VA-based research program to improve Veteran health and well- being.