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Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder

Molecular Psychiatry volume 18, pages 922–929 (2013)Cite this article

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Abstract

Several genome-wide association studies for bipolar disorder (BD) have found a strong association of the Ankyrin 3 (ANK3) gene. This association spans numerous linked single-nucleotide polymorphisms (SNPs) in an ∼250-kb genomic region overlapping ANK3. The associated region encompasses predicted regulatory elements as well as two of the six validated alternative first exons, which encode distinct protein domains at the N-terminus of the protein also known as Ankyrin-G. Using RNA ligase-mediated rapid amplification of cDNA ends to identify novel transcripts in conjunction with a highly sensitive, exon-specific multiplexed mRNA expression assay, we detected differential regulation of distinct ANK3 transcription start sites and coupling of specific 5′ ends with 3′ mRNA splicing events in postmortem human brain and human stem cell-derived neural progenitors and neurons. Furthermore, allelic variation at the BD-associated SNP rs1938526 correlated with a significant difference in cerebellar expression of a brain-specific ANK3 transcript. These findings suggest a brain-specific cis-regulatory transcriptional effect of ANK3 that may be relevant to BD pathophysiology.

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Acknowledgements

We gratefully acknowledge the Stanley Medical Research Institute (Maree Webster) for providing RNA and tissue samples from their postmortem human brain collection and the Massachusetts General Hospital Brain Bank (Charles Vanderburg) for generously providing postmortem human brain samples. Funding was provided by the Stanley Medical Research Institute and from the National Institute Of Mental Health (R33MH087896). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institute Of Mental Health or the National Institutes of Health. We thank Drs Tracey Petryshen and Melanie Leussis for ongoing discussions and helpful review of this manuscript, and Leslie Gaffney for editorial assistance in preparing the figures for publication.

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Authors and Affiliations

  1. Psychiatric and Neurodevelopmental Genetics Unit, Center for Human Genetics, Research, Massachusetts General Hospital, Boston, MA, USA

    E H Rueckert, D Ruderfer, S E Bergen, S M Purcell & S J Haggarty

  2. Department of Psychiatry, Harvard Medical School, Boston, MA, USA

    E H Rueckert, D Ruderfer, S E Bergen, S M Purcell & S J Haggarty

  3. Stanley Center for Psychiatric Research, Broad Institute of MIT and Harvard, Cambridge, MA, USA

    E H Rueckert, D Barker, D Ruderfer, S E Bergen, C O'Dushlaine, C J Luce, K Chambert, J Moran, S M Purcell, J M Madison & S J Haggarty

  4. Analytic Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, USA

    D Ruderfer & S M Purcell

  5. Department of Psychiatry, Mount Sinai School of Medicine, New York, NY, USA

    D Ruderfer, S M Purcell & P Sklar

  6. Department of Neurology, Harvard Medical School, Boston, MA, USA

    S D Sheridan, K M Theriault & S J Haggarty

  7. Center for Human Genetics Research, Massachusetts General Hospital, Boston, MA, USA

    E H Rueckert, S D Sheridan, K M Theriault & S J Haggarty

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  1. E H Rueckert
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Correspondence to S J Haggarty or P Sklar.

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Rueckert, E., Barker, D., Ruderfer, D. et al. Cis-acting regulation of brain-specific ANK3 gene expression by a genetic variant associated with bipolar disorder. Mol Psychiatry 18, 922–929 (2013). https://doi.org/10.1038/mp.2012.104

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