Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
Publication date
2022-05
Authors
Palmer, Duncan S
Howrigan, Daniel P
Chapman, Sinéad B
Adolfsson, Rolf
Bass, Nick
Blackwood, Douglas
Boks, Marco P.
Chen, Chia-Yen
Churchhouse, Claire
Corvin, Aiden P
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Supervisors
Document Type
Article
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taverne
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.
Keywords
Taverne, Genetics, Journal Article
Citation
Palmer, D S, Howrigan, D P, Chapman, S B, Adolfsson, R, Bass, N, Blackwood, D, Boks, M P M, Chen, C-Y, Churchhouse, C, Corvin, A P, Craddock, N, Curtis, D, Di Florio, A, Dickerson, F, Freimer, N B, Goes, F S, Jia, X, Jones, I, Jones, L, Jonsson, L, Kahn, R S, Landén, M, Locke, A E, McIntosh, A M, McQuillin, A, Morris, D W, O'Donovan, M C, Ophoff, R A, Owen, M J, Pedersen, N L, Posthuma, D, Reif, A, Risch, N, Schaefer, C, Scott, L, Singh, T, Smoller, J W, Solomonson, M, Clair, D S, Stahl, E A, Vreeker, A, Walters, J T R, Wang, W, Watts, N A, Yolken, R, Zandi, P P & Neale, B M 2022, 'Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia', Nature Genetics, vol. 54, no. 5, pp. 541-547. https://doi.org/10.1038/s41588-022-01034-x