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_meta = 0.013) and fractalkine(CX3CL1) (OR = 0.92, P_IVW = 0.040) significantly reduced the risk of SCZ, whereas Delta and Notch-like epidermal growth factor-related receptor (DNER) (OR = 1.07, P_meta = 0.007) and eukaryotic translation initiation factor 4E-binding protein 1 (EIF4EBP1)(OR = 1.09, P_IVW = 0.015) was associated with an increased risk of SCZ. For MDD, fibroblast growth factor 23 (FGF23) (OR = 0.97, P_meta = 0.015) and interleukin-20 (IL20) (OR = 0.96, P_IVW = 0.028) significantly reduced the risk, whereas tumor necrosis factor ligand superfamily member 12 (TNFSF12) was associated with an increased risk of MDD (OR = 1.02, P_meta = 0.039). In BD, elevated circulating levels of C-X-C motif chemokine 5 (CXCL5) (OR = 0.95, P_IVW = 0.024), TRANCE (OR = 0.95, P_meta = 0.016), and CC motif chemokine ligand 7 (CCL7) (OR = 0.94, P_meta = 0.023) were significantly associated with reduced risk, suggesting potential protective effects. In multivariable MR analysis, after adjusting for other inflammatory protein levels, CRP showed a significant protective effect on SCZ (OR = 0.91, P_IVW = 0.008), FGF23 demonstrated a significant protective effect on MDD (OR = 0.96, P_IVW = 0.038), and TNFSF12 significantly increased the risk of MDD (OR = 1.03, P_IVW = 0.032). Colocalization analysis provided strong evidence for shared genetic variants between DNER and SCZ (PH4 = 0.89), with the rs35975053 locus being the most significant. This MR study suggests potential causal links between inflammatory proteins and psychiatric disorders. CRP and CX3CL1 were protective for SCZ, while DNER and EIF4EBP1 increased risk. FGF23 and IL20 were protective for MDD, whereas TNFSF12 increased risk. CXCL5, TRANCE, and CCL7 were suggestively protective for BD. The shared causal genetic variants between DNER and SCZ suggest a mechanism underlying neuropsychiatric pathogenesis. Further experimental studies are warranted to elucidate the underlying biological mechanisms and identify novel diagnostic biomarkers and therapeutic targets.