Potential therapeutic targets for common mental disorders identified through Mendelian randomization and colocalization

Abstract Mental disorders are a major global health challenge, exacerbated by a narrow range of effective treatments and inadequate responses. The discovery of novel drug targets is necessary. We leveraged genome-wide association study summary statistics for 6 mental disorders (anorexia nervosa (AN), post-traumatic stress disorder (PTSD), attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BIP), sample sizes ranging from 72,517 to 500,199) and quantitative trait loci summary statistics of 713 proteins in cerebrospinal fluid (CSF) to investigate genetic relationships between CSF protein and the mental disorders. Two-sample Mendelian randomization (MR) analysis with the Wald ratio method revealed that the expression of 17, 13, 16, 24, 36, and 27 proteins had potential causal effects on the 6 mental disorders AN, PTSD, ADHD, MDD, SCZ, and BIP, respectively ( P < 0.05). Among these, Bayesian colocalization suggested a shared genetic etiology among several proteins (posterior probability > 0.70), including PGD with AN, LGALS9 with PTSD, SERPING1 with MDD, AGRP with SCZ, and FOLH1 and HGFAC with BIP, whereas no protein showed colocalization with ADHD. Protein-protein interaction was obtained to identify potential molecular interactions among these proteins. A total of 18 drug compunds that target these proteins were obtained in DrugBank. This study provides genetics-informed target prioritization for mental disorders.