Journal article

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 AL Hall, Joel E Kleinman, Thomas Hyde, Daniel R Weinberger, Paul J Harrison, Wilfried Haerty, Elizabeth M Tunbridge

Molecular Psychiatry | Springer Science and Business Media LLC | Published : 2019

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 pre..

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University of Melbourne Researchers

Grants

Awarded by Wellcome Trust


Awarded by UK Medical Research Council


Awarded by Australian National Health and Medical Research Council (NHMRC)


Awarded by BBSRC, Institute Strategic Programme Grant


Awarded by BBSRC Core Strategic Programme Grant


Funding Acknowledgements

We are grateful to Li Chen and Arne Mould for technical assistance. This research was supported by a Wellcome Trust [201879/Z/16/Z] award to MBC and a UK Medical Research Council [MR/P026028/1] award to EMT. The authors wish to acknowledge the following funding sources: MBC is supported by an Australian National Health and Medical Research Council (NHMRC) Early Career Fellowship [APP1072662]. EMT is supported by a Royal Society University Research Fellowship. WH and TW are supported by the BBSRC, Institute Strategic Programme Grant [BB/J004669/1], BBSRC Core Strategic Programme Grant [BB/P016774/1]. This study was supported by the National Institute for Health Research Oxford Health Biomedical Research Centre. The human brain tissue repository is supported by the Lieber Institute for Brain Development. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR or the Department of Health. The contents of the published material are solely the responsibility of the administering institution, a participating institution, or individual authors and do not reflect the views of NHMRC.