Comparative Analysis of Variant Distribution in Schizophrenia-Associated Genes

Abstract

Schizophrenia is a complex neuropsychiatric disorder affecting approximately one percent of the global population, with heritability estimates reaching eighty percent. While recent large-scale genomic studies have identified numerous risk loci, systematic analysis of variant distribution patterns across key candidate genes remains limited. This study presents a comprehensive comparative analysis of variant distribution patterns across six schizophrenia-associated genes using data from the SCHEMA consortium. We analyzed 4,180 genetic variants from CACNA1C, COMT, DAOA, DISC1, GRM3, and NRG1 genes to determine gene-specific functional constraint patterns and their implications for disease mechanisms. Our analysis reveals dramatic differences in functional constraint across genes, with DAOA exhibiting the highest proportion of high-impact variants at 7.73 percent compared to NRG1 at 0.49 percent, representing a 15.8-fold difference in tolerance to functional disruption. We quantified distributional heterogeneity using multiple metrics, finding a fold difference of 7.76 times in variant burden, coefficient of variation of 70.24 percent, and clear gene-specific constraint signatures. Notably, genes involved in neurotransmitter regulation such as DAOA and COMT showed higher functional constraint than those involved in neurodevelopment including NRG1 and CACNA1C, suggesting distinct pathogenic mechanisms. These findings provide novel insights into the genetic architecture of schizophrenia and establish a framework for prioritizing variants in precision psychiatry applications.