Genomics-driven integrative analysis highlights immune-related plasma proteins for psychiatric disorders

Background: Genome-wide association studies (GWAS) have identified numerous variants associated with psychiatric disorders. However, it remains largely unknown on how GWAS risk variants contribute to psychiatric disorders.

Methods: Through integrating two largest, publicly available, independent protein quantitative trait loci datasets of plasma protein and nine large-scale GWAS summary statistics of psychiatric disorders, we first performed proteome-wide association study (PWAS) to identify psychiatric disorders-associated plasma proteins, followed by enrichment analysis to reveal the underlying biological processes and pathways. Then, we conducted Mendelian randomization (MR) and Bayesian colocalization (COLOC) analyses, with both discovery and parallel replication datasets, to further identify protein-disorder pairs with putatively causal relationships. We finally prioritized the potential drug targets using Drug Gene Interaction Database.

Results: PWAS totally identified 112 proteins, which were significantly enriched in biological processes relevant to immune regulation and response to stimulus including regulation of immune system process (adjusted P = 1.69 × 10^-7) and response to external stimulus (adjusted P = 4.13 × 10^-7), and viral infection related pathways, including COVID-19 (adjusted P = 2.94 × 10^-2). MR and COLOC analysis further identified 26 potentially causal protein-disorder pairs in both discovery and replication analysis. Notably, eight protein-coding genes were immune-related, such as IRF3, CSK, and ACE, five among 16 druggable genes were reported to interact with drugs, including ACE, CSK, PSMB4, XPNPEP1, and MICB.

Conclusions: Our findings highlighted the immunological hypothesis and identified potentially causal plasma proteins for psychiatric disorders, providing biological insights into the pathogenesis and benefit the development of preventive or therapeutic drugs for psychiatric disorders.