Palmer, Duncan S;
Howrigan, Daniel P;
Chapman, Sinéad B;
Adolfsson, Rolf;
Bass, Nick;
Blackwood, Douglas;
Boks, Marco PM;
... Neale, Benjamin M; + view all
(2022)
Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia.
Nature Genetics
, 54
pp. 541-547.
10.1038/s41588-022-01034-x.
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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.
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