Revealing potential drug targets in schizophrenia through proteome-wide Mendelian randomization genetic insights

Abstract

Background

Schizophrenia (SCZ) is a severe, chronic mental disorder with no current cure. Identifying novel pharmacological targets is crucial for developing more effective treatments.

Methods

We performed two-sample Mendelian randomization (MR) analyses to estimate the associations between cerebrospinal fluid (CSF) containing 154 proteins and plasma containing 734 proteins and risk of SCZ. Bidirectional MR analysis, steiger filtering, bayesian colocalization, phenotypic scanning, and validation analysis were examined to validate the assumptions of MR. For proteins significantly associated with SCZ identified by MR, we explored their potential impact on brain structures, including cortical surface area (SA), thickness (TH), and the volume of subcortical structures.

Results

MR analysis identified 13 protein-SCZ pairs at Bonferroni significance (P < 5.63 × 10⁻⁵). Notably, the genetically proxied protein level of neuromedin B (NMB) was associated with an increased risk for SCZ (odds ratio [OR] = 1.41; 95 % CI, 1.27 to 1.58; P = 6.68 × 10⁻¹⁰). Bayesian colocalization suggested that NMB shares genetic variations with SCZ. Further, NMB interacts with target proteins of current SCZ drugs and was validated in the UK Biobank. The genetically proxied NMB was positively associated with an increase in the surface area (SA) of the parahippocampal gyrus (β = 8.93 mm², 95 % CI, 1.58 to 16.3, P = .02). Additionally, an increase in the genetically proxied SA of the parahippocampal gyrus was inversely associated with the risk of SCZ (OR = 0.996, 95 % CI, 0.993 to 0.999, P = .04).

Conclusions

The findings suggest that NMB may represent a promising target for pharmacological intervention in SCZ. This warrants further investigation into the specific constituents involved, which could have potential for follow-up studies.