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

Palmer, D. S., Howrigan, D. P., Chapman, S. B., Adolfsson, R., Bass, N., Blackwood, D., Boks, M. P. M., Chen, C., 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, Lisa ORCID: https://orcid.org/0000-0002-5122-8334, 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., St Clair, D., Stahl, E. A., Vreeker, A., Walters, J. T. R., Wang, W., Watts, N. A., Yolken, R., Zandi, P. P. and Neale, B. M. (2022) Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia. Nature Genetics, 54. pp. 541-547. ISSN 1546-1718 (online) 1061-4036 (print)

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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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