Uncovering bi-directional causal relationships between plasma proteins and psychiatric disorders: A proteome-wide study and directed network analysis

Psychiatric disorders represent a major public health burden yet their etiologies remain poorly understood, and treatment advances are limited. In addition, there are no reliable biomarkers for diagnosis or progress monitoring. Here we performed a proteome-wide causal association study covering 3522 plasma proteins and 24 psychiatric traits or disorders, based on large-scale GWAS data and the principle of Mendelian randomization (MR). We have conducted ~95,000 MR analyses in total; to our knowledge, this is the most comprehensive study on the causal relationship between plasma proteins and psychiatric traits. The analysis was bi-directional: we studied how proteins may affect psychiatric disorder risks, but also looked into how psychiatric traits/disorders may be causal risk factors for changes in protein levels. We also performed a variety of additional analysis to prioritize protein-disease associations, including HEIDI test for distinguishing functional association from linkage, analysis restricted to cis- acting variants and replications in independent datasets from the UK Biobank. Based on the MR results, we constructed directed networks linking proteins, drugs and different psychiatric traits, hence shedding light on their complex relationships and drug repositioning opportunities. Interestingly, many top proteins were related to inflammation or immune functioning. The full results were also made available online in searchable databases. In conclusion, identifying proteins causal to disease development have important implications on drug discovery or repurposing. Findings from this study may also guide the development of blood-based biomarkers for the prediction or diagnosis of psychiatric disorders, as well as assessment of disease progression or recovery.