Circulating inflammatory proteins associated with risks of schizophrenia, bipolar disorder, and major depressive disorder: a mendelian randomization study.

Schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD) share common genetic and environmental risk factors, with immune-inflammatory dysregulation playing a crucial role in their pathophysiology. However, further research is needed to clarify causal relationships. We conducted a Mendelian randomization (MR) study using summary statistics from large-scale genome-wide association studies (GWAS) of European ancestry as instrumental variables to assess the association between 95 circulating inflammatory proteins and the risk of SCZ, BD, and MDD. Initially, a bidirectional two-sample MR analysis was performed to clarify the direction of causality. Subsequently, multivariable MR analysis was employed to investigate whether the effects of different circulating proteins on psychiatric disorders exhibit complex overlap or interrelated effects. Finally, colocalization analysis was applied to determine whether circulating proteins share causal genetic variants with psychiatric disorders. To enhance the robustness of our findings, a series of sensitivity analyses were conducted, including tests for horizontal pleiotropy, heterogeneity, and rigorous quality control procedures. Discovery analyses were based on data from the Psychiatric Genomics Consortium (PGC), while validation was performed using data from the FinnGen biobank. Meta-analysis was used to integrate results from multiple data sources. Evidence strength was evaluated based on consistency across MR, replication, and colocalization. Forward univariable MR and meta-analysis revealed that elevated circulating C-reative protein (CRP) (OR = 0.93, P