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

Palmer, Duncan, Howrigan, Daniel, Chapman, Sinead, Adolfsson, Rolf, Bass, Nick, Blackwood, Douglas, Boks, Marco, Chen, Chia-Yen, Churchhouse, Claire, Corvin, Aiden, Craddock, Nicholas ORCID: https://orcid.org/0000-0003-2171-0610, Curtis, David, Di Florio, Arianna ORCID: https://orcid.org/0000-0003-0338-2748, Dickerson, Faith, Freimer, Nelson, Goes, Fernando, Jia, Xiaoming, Jones, Ian ORCID: https://orcid.org/0000-0001-5821-5889, Jones, Lisa ORCID: https://orcid.org/0000-0001-5821-5889, Jonsson, Lina, Kahn, Rene, Landen, Mikael, Locke, Adam, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, O'Donovan, Michael ORCID: https://orcid.org/0000-0001-7073-2379, Ophoff, Roel, Owen, Michael ORCID: https://orcid.org/0000-0003-4798-0862, Pedersen, Nancy, Posthuma, Danielle, Reif, Andreas, Risch, Neil, Schaefer, Catherine, Scott, Laura, Singh, Tarjinder, Smoller, Jordan, Solomonson, Matthew, St Clair, David, Stahl, Eli, Vreeker, Annabel, Walters, James ORCID: https://orcid.org/0000-0002-6980-4053, Wang, Weiqing, Watts, Nicholas, Yolken, Robert, Zandi, Peter and Neale, Benjamin 2022. Exome sequencing in bipolar disorder reveals AKAP11 as a risk gene shared with schizophrenia. Nature Genetics 10.1038/s41588-022-01034-x

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Abstract

We report results from the Bipolar Exome (BipEx) collaboration analysis of whole-exome sequencing of 13,933 patients with bipolar disorder (BD) matched with 14,422 controls. We find an excess of ultra-rare protein-truncating variants (PTVs) in patients with BD among genes under strong evolutionary constraint in both major BD subtypes. We find enrichment of ultra-rare PTVs within genes implicated from a recent schizophrenia exome meta-analysis (SCHEMA; 24,248 cases and 97,322 controls) and among binding targets of CHD8. Genes implicated from genome-wide association studies (GWASs) of BD, however, are not significantly enriched for ultra-rare PTVs. Combining gene-level results with SCHEMA, AKAP11 emerges as a definitive risk gene (odds ratio (OR) = 7.06, P = 2.83 × 10−9). At the protein level, AKAP-11 interacts with GSK3B, the hypothesized target of lithium, a primary treatment for BD. Our results lend support to BD’s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	National Centre for Mental Health (PNCMH) Medicine Neuroscience and Mental Health Research Institute (NMHRI) MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Publisher:	Nature Research
ISSN:	1061-4036
Date of First Compliant Deposit:	20 September 2021
Date of Acceptance:	15 February 2022
Last Modified:	07 Nov 2023 11:39
URI:	https://orca.cardiff.ac.uk/id/eprint/144297

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