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

Area of Science:

• Neuroscience
• Immunology
• Psychiatry

Background:

• Inflammatory proteins are linked to psychiatric disorders, but causal relationships and mechanisms are not fully understood.
• Investigating the role of specific inflammatory proteins in psychiatric conditions is crucial for understanding disease etiology.

Purpose of the Study:

• To investigate the causal relationship between 91 inflammatory proteins and 11 psychiatric disorders using a bidirectional Mendelian randomization approach.
• To explore potential mediating roles of brain imaging-derived phenotypes in the observed associations.

Main Methods:

• Bidirectional Mendelian randomization (MR) analysis utilizing genetic variants from large-scale genome-wide association studies (GWAS).
• Included 91 inflammatory proteins (N=14,824) and 11 psychiatric disorders (N=9725 to 1,035,760).
• Employed inverse variance weighted (IVW) method for primary analysis and sensitivity analyses; two-step MR assessed mediation by brain imaging-derived phenotypes (IDPs).

Main Results:

• Forward MR revealed a protective effect of CD40 on schizophrenia (SCZ) and bipolar disorder (BD).
• Reverse MR indicated an association between increased genetic risk for Tourette's syndrome (TS) and reduced Fms-associated tyrosine kinase 3 ligand (Flt3L) levels.
• The protective effect of CD40 on SCZ was partially mediated by fractional anisotropy (FA) in the superior frontal occipital fasciculus.

Conclusions:

• CD40 demonstrates an immunoprotective effect on SCZ and BD.
• Partial mediation of CD40's effect on SCZ by FA values in the superior frontal occipital fasciculus was observed.
• Findings contribute to understanding the etiology of psychiatric disorders and highlight potential therapeutic targets involving inflammatory proteins.