Investigating shared genetic architecture between major depressive disorder and central obesity.

Abstract

This study investigated the shared genetic architecture between major depressive disorder (MDD) and waist-hip ratio (WHR) to provide insights into the biological mechanisms underlying their comorbidity. Using large-scale genome-wide association study summary statistics, we performed cross-trait genetic correlation and pleiotropic variant discovery analyses and bidirectional Mendelian randomization analysis, as well as drug target prioritization analysis. We identified significant genetic correlation between MDD and WHR (r _g = 0.11, p = 4.18 × 10^-5). Cross-trait analysis identified 26 pleiotropic loci, including a novel variant (rs2855812, intronic to MICB). Colocalization analysis confirmed six pleiotropic loci. Forward Mendelian randomization analysis demonstrated MDD is associated with increased WHR (β = 0.079, 95% CI: 0.014-0.143; p = 0.017), with no reverse causation. Drug prioritization identified agents able to be repurposed targeting MICB, PSORS1C1, and C6orf15. Enrichment analyses highlighted immune pathways. Our findings establish pleiotropy between MDD and WHR, implicating dysregulated immunometabolic pathways as shared mechanisms. Prioritized drug targets represent translatable opportunities for comorbidity management.