Proteome-wide multi-trait association analyses prioritize candidate proteins and therapeutic targets for psychiatric...

Genome-wide association studies (GWAS) have identified numerous risk loci for psychiatric disorders, yet their limited explanatory power and unresolved molecular mechanisms impede therapeutic development. While proteomics has emerged as a key tool for elucidating genetic risk mechanisms, prior studies have been constrained by single-trait analyses and limited sample sizes. In this study, we performed multi-trait analysis of GWASs (MTAG) analyses on ten major psychiatric disorders by leveraging the large scale GWAS summary statistics (N = 14,307 to 2,000,702). MTAG significantly enhanced discovery power for shared genetic architecture, increasing the effective sample size by 56.55 % on average and identifying an average of 68 additional genetic loci per disorder. We then performed multi-trait proteome-wide association studies (PWAS) by combining MTAG results with human brain proteomic data from ROS/MAP and Banner cohorts (N = 528), identifying 137 genetically regulated proteins associated with bipolar disorder (43), major depressive disorder (46), schizophrenia (60), ADHD (18), anxiety (30), and PTSD (52). Through causal inference analyses, we prioritized 54 potential causal proteins, including 26 candidates (such as LSM6, GOPC, P2RX7) absent in original GWAS findings. Drug repurposing analyses nominated 32 compounds, including belinostat and vorinostat, that counteract risk-associated expression patterns, alongside 164 clinically actionable drug-protein interactions. Our study provides a mechanistic framework linking genetic risk to brain protein dysregulation and proposes tractable therapeutic targets for psychiatric disorders.