期刊
MOLECULAR PSYCHIATRY
卷 25, 期 1, 页码 37-47出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41380-019-0583-1
关键词
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资金
- Wellcome Trust [201879/Z/16/Z]
- UK Medical Research Council [MR/P026028/1]
- Australian National Health and Medical Research Council (NHMRC) [APP1072662]
- Royal Society University Research Fellowship
- BBSRC, Institute Strategic Programme Grant [BB/J004669/1]
- BBSRC Core Strategic Programme Grant [BB/P016774/1]
- National Institute for Health Research Oxford Health Biomedical Research Centre
- Lieber Institute for Brain Development
- BBSRC [BBS/E/T/000PR6193, BBS/E/T/000PR9819, BBS/E/T/000PR5885] Funding Source: UKRI
- MRC [MR/P026028/1] Funding Source: UKRI
RNA splicing is a key mechanism linking genetic variation with psychiatric disorders. Splicing profiles are particularly diverse in brain and difficult to accurately identify and quantify. We developed a new approach to address this challenge, combining long-range PCR and nanopore sequencing with a novel bioinformatics pipeline. We identify the full-length coding transcripts of CACNA1C in human brain. CACNA1C is a psychiatric risk gene that encodes the voltage-gated calcium channel Ca(v)1.2. We show that CACNA1C's transcript profile is substantially more complex than appreciated, identifying 38 novel exons and 241 novel transcripts. Importantly, many of the novel variants are abundant, and predicted to encode channels with altered function. The splicing profile varies between brain regions, especially in cerebellum. We demonstrate that human transcript diversity (and thereby protein isoform diversity) remains under-characterised, and provide a feasible and cost-effective methodology to address this. A detailed understanding of isoform diversity will be essential for the translation of psychiatric genomic findings into pathophysiological insights and novel psychopharmacological targets.
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