A causal coding variant regulating alternative splicing of DOC2A at 16p.11.2 GWAS locus influences susceptibility to...

Although genome-wide association studies (GWASs) have identified many schizophrenia-associated variants, their biological mechanisms remain unclear. Using transcriptomic data from human brain tissues, we performed splicing quantitative trait locus (sQTL) analyses of schizophrenia-associated single-nucleotide polymorphisms and identified more than 17,000 sQTLs linked to previously unidentified splicing junctions. Functional prioritization and experimental validation highlighted the synonymous variant rs3935873 within the 16p11.2 GWAS locus strongly associated with an unannotated isoform DOC2A^{∆Val217-Pro218}. rs3935873 was significantly associated with hippocampal volume, and hippocampal overexpression of DOC2A^{∆Val217-Pro218} in mice recapitulated schizophrenia-relevant behavioral deficits, phenotypes absent in DOC2A^Full-Length-overexpressing mice. Overexpression of both isoforms altered excitatory synaptic transmission, structural modeling revealed divergent tertiary configurations between DOC2A^{∆Val217-Pro218} and DOC2A^Full-Length, and interactome profiling highlighted that DOC2A^{∆Val217-Pro218} unique interactors are enriched in the myosin II complex and ankyrin binding, suggesting the acquisition of previously unknown structural and regulatory functions by DOC2A^{∆Val217-Pro218}. Our study implicates dysregulated splicing in DOC2A as a functional mechanism for schizophrenia genetic risk and demonstrates how unannotated isoforms can reveal disease-relevant pathways.