The Causal Relationships Between Inflammatory Proteins, Brain Structure, and Psychiatric Disorders: A Two-Step Mendelian Randomization Analysis

Background and hypothesis: Inflammatory proteins are implicated in psychiatric disorders, but the causality and underlying mechanisms remain unclear.

Study design: We conducted bidirectional Mendelian randomization (MR) using genetic variants from genome-wide association studies (GWAS) for 91 inflammatory proteins (N = 14 824) and 11 psychiatric disorders (N = 9725 to 1 035 760). The primary analysis used the inverse variance weighted (IVW) method, with additional sensitivity analyses to confirm robustness. A two-step MR approach assessed whether brain imaging-derived phenotypes (IDPs) mediated the observed effects.

Study results: Forward MR analysis found the protective effect of CD40 on schizophrenia (SCZ) (IVW OR = 0.90, P = 5.29 × 10-6) and bipolar disorder (BD) (IVW OR = 0.89, P = 5.08 × 10-6). Reverse MR demonstrated that increased genetic risk of Tourette's syndrome (TS) was associated with reduced Fms-associated tyrosine kinase 3 ligand (Flt3L) levels (Flt3L) (Wald Ratio beta = -0.42, P = 1.99 × 10-7). The protective effect of CD40 on SCZ was partially mediated by the modulation of fractional anisotropy (FA) values in the right and left superior frontal occipital fasciculus, with mediation proportions of 9.6% (P = .025) and 11.5% (P = .023), respectively.

Conclusion: CD40 exerts an immunoprotective effect on SCZ and BD, and the effect of CD40 on SCZ was partially mediated through modulation of FA values in the superior frontal occipital fasciculus. These findings enhance comprehension of the etiology of these psychiatric conditions and underscore the promise of therapeutic strategies aimed at inflammatory proteins.