Long-read sequencing reveals the complex splicing profile of the psychiatric risk gene CACNA1C in human brain

Michael B. Clark, Tomasz Wrzesinski, Aintzane B. Garcia, Nicola A.L. Hall, Joel E. Kleinman, Thomas Hyde, Daniel R. Weinberger, Paul J. Harrison, Wilfried Haerty, Elizabeth M. Tunbridge

Research output: Contribution to journalArticle

Abstract

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 CaV1.2. 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.

Original languageEnglish (US)
Pages (from-to)37-47
Number of pages11
JournalMolecular psychiatry
Volume25
Issue number1
DOIs
StatePublished - Jan 1 2020

ASJC Scopus subject areas

  • Molecular Biology
  • Psychiatry and Mental health
  • Cellular and Molecular Neuroscience

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