Context-specific expression quantitative trait loci dynamics uncover genetic pleiotropy in schizophrenia

Schizophrenia (SCZ) is a highly heritable psychiatric disorder, yet the mechanisms linking genetic risk to pathogenesis remain unclear. This study employs context-specific expression quantitative trait loci (eQTL) analysis using the BrainSeq Phase 1 dataset to dissect schizophrenia-associated regulatory dynamics. We identified widespread loss and gain of regulatory associations in schizophrenia group versus controls, alongside consistent eQTLs. A notable target gene switching phenomenon emerged, where specific SNPs regulated distinct genes across disease states, indicative of genetic pleiotropy mediated by competition for shared regulatory elements. Pleiotropic SNPs exhibited stronger schizophrenia associations, localized farther from target genes, and were enriched in repressive chromatin domains marked by H3K27me3. Transcription factor binding site analysis implicated EZH2, a polycomb repressive complex component, in mediating these regulatory shifts. Integration of schizophrenia-specific eQTLs with GWAS data via Mendelian Randomization prioritized risk genes like ANKRD45, which showed disease-context regulation and links to behavioral deficits. Overexpression of ANKRD45 inhibited neuronal differentiation, whereas knockdown promoted it. This study presents context-specific eQTL dynamics as a crucial factor in the genetic landscape of schizophrenia, enhancing our understanding of non-coding risk variants and their role in disease susceptibility, and emphasizing the importance of utilizing context-specific eQTL data in elucidating the mechanisms of mental illness.