Circulating Blood-Based Proteins in Psychopathology and Cognition: A Mendelian Randomization Study

Area of Science:

• Psychiatric Genetics
• Proteomics
• Biomarker Discovery

Background:

• Peripheral biomarkers for psychiatric disorders are needed for improved diagnosis and treatment.
• Traditional studies face confounds from treatment and exposures.
• Large-scale 2-sample Mendelian randomization (MR) can assess causal protein effects on neuropsychiatric phenotypes.

Purpose of the Study:

• To identify circulating proteins associated with risk for schizophrenia (SCZ), bipolar disorder (BD), and major depressive disorder (MDD).
• To identify circulating proteins associated with cognitive task performance (CTP).

Main Methods:

• Utilized a 2-sample MR design with proteomic quantitative trait loci from UK Biobank and deCODE Genetics.
• Analyzed summary statistics from large-scale genome-wide association studies for SCZ, BD, MDD, and CTP.
• Performed pathway, protein-protein interaction, and drug target enrichment analyses on significant associations.

Main Results:

• Identified 113 significant associations (46 novel) involving 91 proteins across the four phenotypes.
• Observed pleiotropic effects of immune-related proteins (e.g., interleukins, complement factors) across multiple phenotypes.
• Drug target enrichment suggested repurposing anti-inflammatory agents for SCZ, amantadine for BD, retinoic acid for MDD, and duloxetine for CTP.

Conclusions:

• Potentially causal effects of circulating proteins on neuropsychiatric phenotypes suggest novel biomarkers.
• Findings offer insights for developing innovative therapeutic strategies.
• Pleiotropic effects indicate shared etiology among psychiatric conditions and cognitive function.