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 JournalArticleAcademicpeer-review

3 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)541-547
Number of pages7
JournalNature Genetics
Volume54
Issue number5
Early online date11 Apr 2022
DOIs
Publication statusPublished - May 2022

Cite this