Identifying novel protein biomarkers with cross-psychiatric disorders effects and potential intervention targets: Evidence from proteomic-Mendelian randomization

Abstract

Plasma proteins are the potential therapeutic targets for psychiatric disorders due to their important roles in signal transduction. We aimed to explore the plasma protein biomarkers with cross-psychiatric disorders effects. Proteome-wide Mendelian randomization (MR) and colocalization analyses were performed to investigate the potential causal relationship between plasma protein biomarkers and 12 psychiatric disorders and further identify the potential proteins with cross-effects. To assess the directionality and exclude potential reverse causation, Steiger directionality tests and reverse MR analyses were additionally conducted. Then, validation analysis was performed by employing summary data from cross-psychiatric disorder GWAS to validate the cross-psychiatric effects of proteins. Protein-protein interactions were conducted to evaluate the interaction between candidate proteins and druggability assessment was used to prioritize potential drug targets for psychiatric disorders. We identified novel plasma proteins that possessed cross-psychiatric disorder effects, especially BTN2A1 and BTN3A2 associated with major depressive disorder (MDD), schizophrenia (SCZ), and bipolar disorder (BIP); ITIH1, ITIH3, ITIH4 and FES associated with SCZ and BIP, and the cross-effects of these proteins on SCZ and BIP were confirmed by validation analyses. Steiger tests and reverse MR supported causal directionality. Besides, the protein-protein interactions (PPI) analysis indicated cross-effects proteins had significant interaction, especially ITIH1-ITIH3. The druggability assessment prioritized eight proteins, two of which (ITIH3 and NCAM1) has been targeted by antipsychotic drugs. Our findings provided insights into shared biological mechanisms underlying these conditions.