학술논문
Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia
Document Type
article
Author
Palmer, Duncan S; Howrigan, Daniel P; Chapman, Sinéad B; Adolfsson, Rolf; Bass, Nick; Blackwood, Douglas; Boks, Marco PM; Chen, Chia-Yen; Churchhouse, Claire; Corvin, Aiden P; Craddock, Nicholas; Curtis, David; Di Florio, Arianna; Dickerson, Faith; Freimer, Nelson B; Goes, Fernando S; Jia, Xiaoming; Jones, Ian; Jones, Lisa; Jonsson, Lina; Kahn, Rene S; Landén, Mikael; Locke, Adam E; McIntosh, Andrew M; McQuillin, Andrew; Morris, Derek W; O’Donovan, Michael C; Ophoff, Roel A; Owen, Michael J; Pedersen, Nancy L; Posthuma, Danielle; Reif, Andreas; Risch, Neil; Schaefer, Catherine; Scott, Laura; Singh, Tarjinder; Smoller, Jordan W; Solomonson, Matthew; Clair, David St; Stahl, Eli A; Vreeker, Annabel; Walters, James TR; Wang, Weiqing; Watts, Nicholas A; Yolken, Robert; Zandi, Peter P; Neale, Benjamin M
Source
Nature Genetics. 54(5)
Subject
Language
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.