An alternative splicing hypothesis for neuropathology of schizophrenia: evidence from studies on historical candidate genes and multi-omics data

Alternative splicing of schizophrenia risk genes, such as DRD2, GRM3, and DISC1, has been extensively described. Nevertheless, the alternative splicing characteristics of the growing number of schizophrenia risk genes identified through genetic analyses remain relatively opaque. Recently, transcript...

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Bibliographic Details
Published in:Molecular psychiatry 2022-01, Vol.27 (1), p.95-112
Main Authors: Zhang, Chu-Yi, Xiao, Xiao, Zhang, Zhuohua, Hu, Zhonghua, Li, Ming
Format: Article
Language:English
Subjects:
Alternative splicing
Alternative Splicing - genetics
Brain
Disc1 protein
Dopamine D2 receptors
Exon skipping
Genetic analysis
Humans
Isoforms
Kruppel-Like Transcription Factors - genetics
Mental disorders
Methyltransferases - genetics
Protein Isoforms - genetics
RNA Splicing
Schizophrenia
Schizophrenia - genetics
Sequence Analysis, RNA
Therapeutic targets
Transcription
Transcriptomes
Transcriptomics
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Summary:Alternative splicing of schizophrenia risk genes, such as DRD2, GRM3, and DISC1, has been extensively described. Nevertheless, the alternative splicing characteristics of the growing number of schizophrenia risk genes identified through genetic analyses remain relatively opaque. Recently, transcriptomic analyses in human brains based on short-read RNA-sequencing have discovered many "local splicing" events (e.g., exon skipping junctions) associated with genetic risk of schizophrenia, and further molecular characterizations have identified novel spliced isoforms, such as AS3MT and ZNF804A . In addition, long-read sequencing analyses of schizophrenia risk genes (e.g., CACNA1C and NRXN1) have revealed multiple previously unannotated brain-abundant isoforms with therapeutic potentials, and functional analyses of KCNH2-3.1 and Ube3a1 have provided examples for investigating such spliced isoforms in vitro and in vivo. These findings suggest that alternative splicing may be an essential molecular mechanism underlying genetic risk of schizophrenia, however, the incomplete annotations of human brain transcriptomes might have limited our understanding of schizophrenia pathogenesis, and further efforts to elucidate these transcriptional characteristics are urgently needed to gain insights into the illness-correlated brain physiology and pathology as well as to translate genetic discoveries into novel therapeutic targets.
ISSN:1359-4184
1476-5578
DOI:10.1038/s41380-021-01037-w