Differential associations of various depression-related phenotypes with cardiometabolic risks: Identification of shared genetic factors and implications for drug repositioning

Abstract

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.

Genetic comorbidity between major depression and cardio-metabolic disease, stratified by age at onset of major depression

“…Twin studies have previously shown genetic overlap between MDD and type 2 diabetes, but evidence from genetic studies has been weaker. The current study, however, does show evidence for a shared genetic aetiology between MDD and type 2 diabetes based on both polygenic risk scores and genetic correlations (21)(22)(23).…”

“…Studies using twin data also showed that the phenotypic association between MDD and type 2 diabetes was partly due to genetic effects (21). This finding has been replicated using a polygenic risk score approach(22), but not using genetic correlations (22,23). The Brainstorm Consortium did not find a significant genetic correlation between MDD and stroke(24), while Wassentheil-Smoller et al(25) showed that higher polygenic risk for MDD was associated with increased risk for stroke, in particular small vessel disease.…”

Rethinking IL-6 and CRP: Why they are more than inflammatory biomarkers, and why it matters

“…Lamers et al, 2016, at 6-year follow-up only). In fact, genetic risk scores for severe melancholic depression seem to be associated with lower risk of adverse cardiac and metabolic symptoms (Wong et al, 2017).…”