Integrating genetic regulation and schizophrenia-specific splicing quantitative expression with GWAS prioritizes novel risk genes for schizophrenia.

Abstract

Alternative splicing (AS) plays a vital role in the pathogenesis of schizophrenia (SCZ). Previous studies have linked the genetic signals from genome-wide association studies (GWAS) with expression quantitative trait loci (eQTL), but the interplay with other genetic regulatory mechanisms, particularly splicing QTL (sQTL), remains unclear. Here, we constructed a comprehensive disease-specific sQTL map to provide genetic variants that could alter gene activity through RNA splicing in SCZ. We analyzed data from 539 SCZ patients, identifying a total of 24,810 significant sQTLs (FDR < 0.05) involving in AS events of 7083 unique genes. By combining this with a large-scale SCZ GWAS, we employed Mendelian randomization (MR) and colocalization analyses to pinpoint 27 significant risk genes with genetic AS regulation that may play a causal role in SCZ. Additional differential splicing analysis of these genes in 539 cases and 754 controls revealed 12 significant genes that may increase SCZ risk due to their AS dysregulation. Notably, five genes (DPYD, LACC1, CCDC122, ANAPC7, and DGKZ) showed consistent splicing regulation effects in both MR analysis and differential splicing analysis. Pathway enrichment analysis of differentially spliced genes revealed potential biologically pathways relevant to SCZ, particularly in synaptic transmission and microtubule movement. Furthermore, single-cell RNA-seq analysis revealed that several genes were preferentially expressed in specific brain cell types, including oligodendrocytes, microglia, and excitatory neurons. Overall, our findings highlight several susceptibility genes that may contribute to SCZ risk by AS regulation. Further characterization of these genes could advance mechanistic understanding and therapeutic discovery for SCZ.