Context-specific eQTL dynamics uncover genetic pleiotropy and chromatin-mediated target gene switching in schizophrenia

Schizophrenia is a highly heritable psychiatric disorder, but functional mechanisms linking genetic risk to pathogenesis remain poorly understood. Most schizophrenia-associated variants reside in non-coding regions, highlighting the need to investigate their regulatory roles. This study employs context-specific expression quantitative trait loci (eQTL) analysis using the BrainSeq Phase I dataset to dissect schizophrenia-associated regulatory dynamics. Comparative eQTL analysis revealed 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 in knockout models. Overall, we found the universality of eQTL specificity, and revealed a new mechanism that multiple genes competing for the shared regulatory sites, leading to phenotype-dependent gene expression shifts. This study establish context-specific eQTL dynamics as a critical layer of schizophrenia's genetic architecture. These insights advance functional interpretation of non-coding risk variants and provide new insights into regulatory mechanisms contributing to disease susceptibility.