Shared genetic architecture between obesity and psychiatric disorders reveals comorbid etiology and therapeutic targets

Abstract Integrated genomic evidence on shared genetic architecture between obesity and psychiatric disorders remains limited. This work utilized multi-level genomic analytic approaches to identify pleiotropic loci, variants, and genes between 14 adiposity traits and 7 psychiatric disorders, including genetic correlation and bidirectional causality as well as gene expression, functional pathway, and druggability, using genome-wide association study data from up to 806,834 European descent individuals. Based on 67 genetically correlated trait pairs established between the two groups, we identified 17 causal shared genes across 26 tissues, which were enriched in neurodevelopment, neuronal function, cellular transport, and developmental biology. Of which NEGR1, CTNNB1, TAOK2, and RTN4RL1 were located in the druggable genome, and CTNNB1 and NT5C2 were clinically actionable. Mendelian randomization further supported extensive bidirectional causal associations. These findings provide robust evidence for a shared genetic etiology between adiposity and psychiatric disorders, underscoring mechanistic links and prioritizing actionable targets for comorbidity intervention.