Genetic Overlap Of Depression With Cardiometabolic Diseases And Implications For Drug Repurposing For Comorbidities

Depression and cardiometabolic diseases, such as coronary artery disease (CAD) and type 2 diabetes (DM), are commonly considered as risk factors to each other. However, little is known about the mechanism underlying the relationship between depression and cardiometabolic traits. Using a polygenic risk score approach, we investigated the genetic overlap of major depressive disorder (MDD) with various cardiometabolic traits based on summary statistics from large-scale meta-analyses of genome-wide association studies (GWAS). GWAS results for MDD were taken from MDD-CONVERGE which represents a relatively homogenous sample of severe depression. We also identified shared genetic variants and inferred the enriched pathways. In addition, we looked for drugs over-represented among the top shared genes, with an aim to finding repositioning opportunities for both kinds of disorders. We found significant polygenic sharing between MDD and cardiometabolic traits, including positive associations with CAD, fat percentage, LDL, triglyceride, body mass index (BMI), waist-hip ratio (WHR) and WHR adjusted for BMI, and an inverse association with HDL. We also observed a modest association of MDD with DM but no significant associations with other glycemic traits or leptin. Some of the shared pathways include lipoprotein metabolism, neurotrophin and oxytocin pathways. Using a gene-set analysis approach, we revealed drugs that may be repositioned for both types of disorders, many of which are supported by previous studies, such as statins, bupropion, verapamil and s-adenosylmethionine. Our study highlights shared genetic bases of MDD with cardiometabolic traits, and implicates the potential of repurposing drugs for comorbidities based on overlapping genetic factors.