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

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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.
Funding Information
  • Stanley Center for Peace and Security
  • U.S. Department of Health & Human Services | National Institutes of Health (R01 CA194393, R37 MH107649, R01 CA194393, R37 MH107649, R01 CA194393, R37 MH107649, R01 CA194393, R37 MH107649, RC2 AG036607, R01 MH085543, RC2 AG036607, R01 MH085542, R01 MH110437, R01 CA194393, R37 MH107649)
  • Dalio Foundation
  • Kent and Elizabeth Dauten
  • Stanley Medical Research Institute
  • U.S. Department of Health & Human Services | NIH | National Institute of Mental Health (U01 MH105578, R01 MH090553, R01 MH095034)
  • RCUK | Medical Research Council (G1000708, MR/P005748/1, MR/P005748/1, MR/L010305/1, MR/P005748/1)

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