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

Duncan S Palmer, Daniel P Howrigan, Sinéad B Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P M Boks, Chia-Yen Chen, Claire Churchhouse, Aiden P Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B Freimer, Fernando S Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina JonssonRene S Kahn, Mikael Landén, Adam E Locke, Andrew M McIntosh, Andrew McQuillin, Derek W Morris, Michael C O'Donovan, Roel A Ophoff, Michael J Owen, Nancy L Pedersen, Danielle Posthuma, Andreas Reif, Neil Risch, Catherine Schaefer, Laura Scott, Tarjinder Singh, Jordan W Smoller, Matthew Solomonson, David St Clair, Eli A Stahl, Annabel Vreeker, James T R Walters, Weiqing Wang, Nicholas A Watts, Robert Yolken, Peter P Zandi, Benjamin M Neale

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.

Original languageEnglish
Pages (from-to)541-547
JournalNature Genetics
Volume54
Issue number5
Early online date11 Apr 2022
DOIs
Publication statusPublished - May 2022

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