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

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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Fig. 1: Case–control enrichment of ultra-rare variants, split by case status and consequence category.
Fig. 2: Biological insights from bipolar case–control whole-exome sequencing data.
Fig. 3: Results of the analysis of ultra-rare PTVs in 13,933 cases and 14,422 controls.

Data availability

We display all of our results, from the variant and gene level, in a browser available at https://bipex.broadinstitute.org. Phenotype curation and QC are available at https://astheeggeggs.github.io/BipEx/. Data are available under the following EGS study accession numbers: EGAS00001005838, EGAS00001005841, EGAS00001005842, EGAS00001005843, EGAS00001005844, EGAS00001005845, EGAS00001005851, EGAS00001005852, EGAS00001005853, EGAS00001005854, EGAS00001005855, EGAS00001005856, EGAS00001005857, EGAS00001005858, EGAS00001005859 and EGAS00001005860. WES data generated under this study are also hosted via the Terra platform (https://app.terra.bio). The Terra environment, created by the Broad Institute, contains a system of workspace functionalities centered on data sharing and analysis. To gain access via Terra, please contact the corresponding authors directly. The GnomAD database can be accessed at gnomad.broadinstitute.org. We used the following pathway databases: Gene Ontology (geneontology.org), KEGG (https://www.genome.jp/kegg) and REACTOME (reactome.org/). GTEx tissue-specific enrichment gene sets are available at data.broadinstitute.org/alkesgroup/LDSCORE/LDSC_SEG_ldscores/.

Code availability

The code used to perform QC, analysis and plot creation is available at github.com/astheeggeggs/BipEx. Data were manipulated using Hail 0.2 and R (4.0.2) using data.table (1.13.0) and dplyr (1.0.1), and plotted with ggplot2 (3.3.2), ggsci (2.9), ggExtra (0.9), ggrepel (0.8.2), RColorBrewer (1.1–2) and gridExtra (2.3) in R (4.0.2).

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Acknowledgements

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.

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Contributions

B.M.N. initiated the project. A.R., A.M.M., A.M., N.B., D.C., R.Y., F.D., D.P., D.S.C., D.W.M., A.C., D.B., F.S.G., J.W.S., M.C.O., M.J.O., M.L., N.L.P., N.C., A.D.F., I.J., L.J., J.W., R.O., M.P.M.B., R.S.K. and R.A. led sample recruitment of the BipEx cohort collection. P.Z., F.S.G., W.W., E.A.S., X.J., C.S., N.R., L.S. and A.E.L. led sample recruitment and curation of the BSC cohorts. X.J., L.S. and A.E.L. curated sample genetic and phenotypic data in the BSC collection. S.B.C. managed sample collections, exome sequencing and data hosting. D.S.P. processed and curated exome sequence data, with assistance from D.P.H., T.S. and B.M.N. D.S.P. processed and curated phenotype data in coordination with A.V. and N.B.F. D.S.P. performed the core analyses in close coordination with B.M.N. and D.P.H. The main findings were interpreted by D.S.P., D.P.H. and B.M.N. M.S. and N.A.W created the bipex.broadinstitute.org browser. A.L. performed gene-based analyses in the BSC dataset. D.S.P. drafted the manuscript in close coordination with D.P.H. and B.M.N., with editing assistance from C.C., A.D.F., A.M., N.A.W., I.J., L.J., L.S., W.W., R.Y., R.O., L.J., M.L., C.-Y.C., D.C., A.V. and F.D. D.S.P., A.D.F., D.C., N.B.F., L.J., R.O., S.B.C., D.P.H. and B.M.N. addressed and responded to reviewer comments.

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Correspondence to Duncan S. Palmer or Benjamin M. Neale.

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Competing interests

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.

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Palmer, D.S., Howrigan, D.P., Chapman, S.B. et al. Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia. Nat Genet 54, 541–547 (2022). https://doi.org/10.1038/s41588-022-01034-x

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