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Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

Palmer, P., Howrigan, D., Chapman, S., Adolfsson, R., Bass, N., Blackwood, D., Boks, M., Chen, C., Churchhouse, C., Corvin, A., Craddock, N., Curtis, D., Di Florio, A., Dickerson, F., Freimer, N., Goes, F., Jia, X., Jones, I., Jones, Lisa ORCID: https://orcid.org/0000-0002-5122-8334, Jonsson, L., Kahn, R., Landen, M., Locke, A., McIntosh, A., McQuillin, A., Morris, D., O'Donovan, M., Ophoff, R., Owen, M., Pedersen, N., Posthuma, D., Reif, A., Risch, N., Schaefer, C., Scott, L., Singh, T., Smoller, J., Solomonson, M., St Clair, D., Stahl, E., Vreeker, A., Walters, J., Wang, W., Watts, N., Yolken, R., Zandi, P. and Neale, B. (2022) Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia. Nature Genetics. ISSN 1546-1718 (online) 1061-4036 (print) (In Press)

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Abstract

Here we report results from the Bipolar Exome (BipEx) collaboration analysis of whole exome sequencing of 13,933 individuals diagnosed with bipolar disorder (BD), matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in BD patients among genes under strong evolutionary constraint, a signal evident in both major BD subtypes, bipolar 1 disorder (BD1) and bipolar 2 disorder (BD2). We also find an excess of ultra-rare PTVs within genes implicated from a recent schizophrenia (SCZ) exome meta-analysis (SCHEMA; 24,248 SCZ cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from GWAS of BD, however, are not significantly enriched for ultra-rare PTVs. Combining BD gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (ultra-rare PTVs seen in 33 BD/SCZ cases and 13 controls, OR = 7.06, P = 2.83 × 10-9). At the protein level, AKAP-11 is known to interact with GSK3B, the hypothesized site of action for lithium, a primary treatment for BD. Overall, our results lend further support to the polygenic basis of BD and demonstrate a role for rare coding variation as a significant risk factor in BD aetiology.

Item Type: Article
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Uncontrolled Discrete Keywords: behavioural genetics, bipolar disorder, DNA sequencing, genetics research, medical genetics
Subjects: B Philosophy. Psychology. Religion > BF Psychology
R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Divisions: College of Health, Life and Environmental Sciences > School of Allied Health and Community
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Depositing User: Katherine Gordon-Smith
Date Deposited: 02 Dec 2021 16:39
Last Modified: 16 May 2022 11:02
URI: https://eprints.worc.ac.uk/id/eprint/11537

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