Alternative splicing of DOC2A gene shown to drive schizophrenia risk

In an important new study, Chinese researchers have discovered the previously unrecognized role of alternative splicing of the DOC2A gene in schizophrenia.

The research was conducted by scientists led by LI Ming from the Kunming Institute of Zoology of the Chinese Academy of Sciences and published in Science Advances on January 16.

Splicing is a process in which RNA is cut and recombined into the final RNA strand that determines how a protein-encoded by DNA-is formed. Different splicing signals for the same RNA strand can generate protein isoforms that function differently. The varied splicing signals may be generated by very small genetic variants in DNA-such as synonymous single nucleotide polymorphisms (SNPs)-that alter a single nucleotide without changing the encoded amino acid sequence.

Although genome-wide association studies (GWAS) have identified thousands of variants associated with schizophrenia, the biological functions related to most of these statistical associations are poorly understood.

To address this problem, the researchers sought to understand how different variants affect splicing and thus produce different protein isoforms.

Using splicing quantitative trait locus (sQTL) analyses of human postmortem brain tissues, the researchers identified more than 17,000 schizophrenia-associated sQTLs across the genome. Among them, the SNP rs3935873 showed the strongest prediction for disrupting DOC2A splicing. Experimental validation confirmed that this variant promotes the expression of a truncated protein isoform, DOC2A△Val217–Pro218, while leaving the full-length transcript unaffected. The isoform was previously unannotated (undocumented).

In murine models, overexpression of this isoform in the hippocampus recapitulated schizophrenia-like behaviors, including anxiety, impaired sensorimotor gating, and anhedonia. These phenotypes were absent in control mice or in mice that expressed full-length DOC2A.

Electrophysiological recordings further revealed enhanced excitatory synaptic transmission, and interactome profiling highlighted distinct molecular pathways, such as myosin II complex enrichment, suggesting altered synaptic functions.

These findings integrate genetic, transcriptomic, and behavioral evidence to underscore the critical role of alternative splicing in the genetic regulation of schizophrenia. They also provide a framework for investigating unannotated isoforms in disease pathogenesis. The study not only describes the functional impact of a specific risk variant but also highlights the significance of isoform-specific mechanisms, suggesting potential avenues for targeted therapeutic strategies.