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

Duncan S. Palmer*, Daniel P. Howrigan, Sinéad B. Chapman, Rolf Adolfsson, Nick Bass, Douglas Blackwood, Marco P.M. Boks, Chia Yen Chen, Claire Churchhouse, Aiden P. Corvin, Nicholas Craddock, David Curtis, Arianna Di Florio, Faith Dickerson, Nelson B. Freimer, Fernando S. Goes, Xiaoming Jia, Ian Jones, Lisa Jones, Lina JonssonRene S. Kahn, Mikael Landén, Adam E. Locke, Andrew M. McIntosh, Andrew McQuillin, Derek W. Morris, Michael C. O’Donovan, Roel A. Ophoff, Michael J. Owen, Nancy L. Pedersen, Danielle Posthuma, Andreas Reif, Neil Risch, Catherine Schaefer, Laura Scott, Tarjinder Singh, Jordan W. Smoller, Matthew Solomonson, David St Clair, Eli A. Stahl, Annabel Vreeker, James T.R. Walters, Weiqing Wang, Nicholas A. Watts, Robert Yolken, Peter P. Zandi, Benjamin M. Neale*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

47 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)541-547
Number of pages7
JournalNature Genetics
Volume54
Issue number5
DOIs
Publication statusPublished - May 2022

Bibliographical note

Funding Information:
This study was supported by the Stanley Family Foundation; Kent and Elizabeth Dauten; National Institutes of Health grants R01 CA194393 (B.M.N.), R37 MH107649 (B.M.N.) and R01 MH085542 (J.W.S.); National Institute of Mental Health grants R01 MH090553 (R.O.), R01 MH095034 (E.A.S.) and U01 MH105578 (N.B.F.); UK Medical Research Council grants G1000708 (A.M.), MR/L010305/1 (M.J.O.) and MR/P005748/1 (M.J.O., M.C.O. and J.W.); ongoing grant support from Stanley Medical Research Institute (F.D., and R.Y.); and The Dalio Foundation (B.M.N.), who have enabled us to rapidly expand our data generation collections with the goal of moving toward better treatments for BD, schizophrenia and other psychiatric disorders. BSC grant support was provided by the National Institutes of Health grants R01 MH110437 (P.Z.), R01 MH085543 (C.S.) and RC2 AG036607 (C.S. and N.R.). We thank W. Ouwehand for contributing control samples for exome sequencing and E. Wigdor for thoughtful comments.

Funding Information:
This study was supported by the Stanley Family Foundation; Kent and Elizabeth Dauten; National Institutes of Health grants R01 CA194393 (B.M.N.), R37 MH107649 (B.M.N.) and R01 MH085542 (J.W.S.); National Institute of Mental Health grants R01 MH090553 (R.O.), R01 MH095034 (E.A.S.) and U01 MH105578 (N.B.F.); UK Medical Research Council grants G1000708 (A.M.), MR/L010305/1 (M.J.O.) and MR/P005748/1 (M.J.O., M.C.O. and J.W.); ongoing grant support from Stanley Medical Research Institute (F.D., and R.Y.); and The Dalio Foundation (B.M.N.), who have enabled us to rapidly expand our data generation collections with the goal of moving toward better treatments for BD, schizophrenia and other psychiatric disorders. BSC grant support was provided by the National Institutes of Health grants R01 MH110437 (P.Z.), R01 MH085543 (C.S.) and RC2 AG036607 (C.S. and N.R.). We thank W. Ouwehand for contributing control samples for exome sequencing and E. Wigdor for thoughtful comments.

Funding Information:
B.M.N. is a member of the scientific advisory board at Deep Genomics and Neumora and a consultant for Camp4 Therapeutics, Takeda Pharmaceutical and Biogen. A.M.M. has received speaker fees from Illumina and Janssen and research grant support from The Sackler Trust. M.L. has received speakers fees from Lundbeck Pharmaceuticals. M.J.O., M.C.O. and J.W. have received a research grant from Takeda Pharmaceuticals outside the scope of the present study. F.S.G. has received a research grant from Janssen Pharmaceuticals outside the scope of the present study. C.-Y.C. is an employee of Biogen. F.D. is an employee of Sheppard Pratt. A.E.L. and E.A.S. are now employees of Regeneron. X.J. is now an employee of Genentech. All other authors declare no competing interests.

Publisher Copyright:
© 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.

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