Cardiff University | Prifysgol Caerdydd ORCA
Online Research @ Cardiff 
WelshClear Cookie - decide language by browser settings

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:, Curtis, David, Di Florio, Arianna ORCID:, Dickerson, Faith, Freimer, Nelson, Goes, Fernando, Jia, Xiaoming, Jones, Ian ORCID:, Jones, Lisa ORCID:, Jonsson, Lina, Kahn, Rene, Landen, Mikael, Locke, Adam, McIntosh, Andrew, McQuillin, Andrew, Morris, Derek, O'Donovan, Michael ORCID:, Ophoff, Roel, Owen, Michael ORCID:, 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:, 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

[thumbnail of 2021 09 DiFlorio combined_2.pdf] PDF - Accepted Post-Print Version
Download (8MB)


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)
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

Citation Data

Cited 6 times in Scopus. View in Scopus. Powered By Scopus® Data

Actions (repository staff only)

Edit Item Edit Item


Downloads per month over past year

View more statistics