Abstract
BACKGROUND: Despite a high heritability of schizophrenia (SZ), only limited variance was attributed to gene loci or the polygenic risk score in genome-wide association studies (GWAS). Early-onset SZ, a more homogeneous SZ subtype, may aid in bridging the genotype-phenotype gap and the identification of its hub genes is critical for early intervention in clinical practice. We aimed to examine the gene expression risk score (GeRS) in patients from both multiplex and simplex families to identify hub genes for early-onset SZ, and perform enrichment analysis to understand the biological functions of the hub genes. METHODS: Based on the GWAS genotype data from patients with SZ in multiplex families (223 early-onset and 372 late-onset) and those from simplex families (matched for sex and onset age), GeRSs for SZ (SZ-GeRSs) were estimated using the SNP-expression prediction model derived from existing brain tissues of patients with psychiatric disorders. Module-based SZ-GeRS was summed over genes from empirically derived gene clusters, network analysis was conducted to identify hub genes, and enrichment analysis was used for functional mapping. RESULTS: Among the 13 modules from existing coexpression analyses of postmortem brains of patients with psychiatric disorders, the meta-analysis revealed that associations with early-onset SZ existed for the GeRS of module 10 in subset, M10(sub)-GeRS (adjusted odds ratio [aOR] = 1.38, 95% CI = 1.22-1.57), and six hub genes, M10(hub)-GeRS (aOR = 1.22, 95% CI = 1.07-1.39), after adjustment for covariates. Functional mapping of the genes revealed their enrichment in excitatory neurons and immune-regulatory pathways. CONCLUSIONS: GeRS for SZ helps identify six hub genes for early-onset schizophrenia, and the enrichment analysis sheds light on their possible roles in the pathophysiology. These findings will enhance the understanding of SZ etiology and may contribute to early screening and personalized prevention efforts.