Multi-level computational analysis identifies schizophrenia missense SNPs with implications for synaptic function, neuroimmune dysfunction, and antipsychotic response.

Schizophrenia (SCZ) has strong genetic underpinnings, yet the functional impact of associated genetic variants remains unclear. We computationally analyzed SCZ-associated missense single-nucleotide polymorphisms (SNPs) from the National Human Genome Research Institute-European Bioinformatics Institute (NHGRI-EBI) Genome-Wide Association Studies (GWAS) Catalog to identify variants with significant functional consequences. From 5083 SCZ-associated SNPs, we prioritized five genes harboring highly deleterious missense SNPs: STX2, BTN2A1, and UGT1A8/9/10. We integrated pathogenicity predictions, protein stability assessments, structural analyses, and protein-protein interaction networks to understand how these SCZ-associated missense variants may contribute to disease pathogenesis. Amino acid changes, or variants, of the five genes were consistently predicted to decrease protein stability. The STX2 variant affects the syntaxin N-terminus domain, crucial for neurotransmitter release and implicated in antipsychotic pharmacology. The BTN2A1 variants disrupt immunoglobulin-like domains involved in T-cell regulation. The UGT1A8/9/10 variant impacts the UDP-glycosyltransferase domain, potentially altering drug metabolism. Protein interaction analyses revealed connections to synaptic signaling, immune regulation, and xenobiotic metabolism pathways implicated in SCZ. Our findings illuminate potential molecular mechanisms by which these genetic variants may contribute to SCZ pathophysiology and highlight promising targets for therapeutic development.