Identifying drug targets for schizophrenia through gene prioritization

Area of Science:

• Genetics
• Neuroscience
• Pharmacology

Background:

• Genome-wide association studies (GWASes) have identified numerous schizophrenia risk loci.
• Previous gene prioritization methods often overlooked genome-wide information, limiting accuracy.

Purpose of the Study:

• To comprehensively identify and prioritize genes involved in schizophrenia etiology.
• To discover novel therapeutic targets for schizophrenia through drug repurposing and development.

Main Methods:

• Applied a combination of locus-based and genome-wide methods to a large GWAS dataset.
• Integrated fine-mapping, distance-based, and gene-based association tests (PoPS, MAGMA).
• Prioritized genes based on existing drug targeting, predicted druggability, and testability in models.

Main Results:

• Prioritized a list of 101 high-confidence schizophrenia-associated genes.
• Identified 15 genes targeted by existing drugs, with 7 not yet tested clinically for psychiatric disorders.
• Highlighted 7 genes predicted to be druggable despite lacking current small molecule inhibitors.
• Found 2 druggable genes in loci shared with addiction GWAS, suggesting shared mechanisms.

Conclusions:

• The curated list of 101 genes provides a valuable resource for understanding schizophrenia pathogenesis.
• Targeting these prioritized genes offers a promising avenue for developing novel schizophrenia therapies.
• Exploring shared genes in addiction models may accelerate drug development for both disorders.