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 Jonsson; Rene 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

doi:10.1038/s41588-022-01034-x

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

School of Medicine

Research output: Contribution to journal › Article › peer-review

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 language	English (US)
Pages (from-to)	541-547
Number of pages	7
Journal	Nature genetics
Volume	54
Issue number	5
DOIs	https://doi.org/10.1038/s41588-022-01034-x
State	Published - May 2022

ASJC Scopus subject areas

Genetics

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Palmer, D. S., Howrigan, D. P., Chapman, S. B., Adolfsson, R., Bass, N., Blackwood, D., Boks, M. P. M., Chen, C. Y., 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, L., ... Neale, B. M. (2022). Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia. Nature genetics, 54(5), 541-547. https://doi.org/10.1038/s41588-022-01034-x

Palmer, DS, Howrigan, DP, Chapman, SB, Adolfsson, R, Bass, N, Blackwood, D, Boks, MPM, Chen, CY, Churchhouse, C, Corvin, AP, Craddock, N, Curtis, D, Di Florio, A, Dickerson, F, Freimer, NB, Goes, FS, Jia, X, Jones, I, Jones, L, Jonsson, L, Kahn, RS, Landén, M, Locke, AE, McIntosh, AM, McQuillin, A, Morris, DW, O’Donovan, MC, Ophoff, RA, Owen, MJ, Pedersen, NL, Posthuma, D, Reif, A, Risch, N, Schaefer, C, Scott, L, Singh, T, Smoller, JW, Solomonson, M, Clair, DS, Stahl, EA, Vreeker, A, Walters, JTR, Wang, W, Watts, NA, Yolken, R , Zandi, PP & Neale, BM 2022, 'Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia', Nature genetics, vol. 54, no. 5, pp. 541-547. https://doi.org/10.1038/s41588-022-01034-x

@article{7b2937a4e58c4b938e5a9587d467720b,

title = "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{\textquoteright}s polygenicity, demonstrating a role for rare coding variation as a significant risk factor in BD etiology.",

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

note = "Publisher Copyright: {\textcopyright} 2022, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2022",

month = may,

doi = "10.1038/s41588-022-01034-x",

language = "English (US)",

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pages = "541--547",

journal = "Nature genetics",

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T1 - Exome sequencing in bipolar disorder identifies AKAP11 as a risk gene shared with schizophrenia

AU - Palmer, Duncan S.

AU - Howrigan, Daniel P.

AU - Chapman, Sinéad B.

AU - Adolfsson, Rolf

AU - Bass, Nick

AU - Blackwood, Douglas

AU - Boks, Marco P.M.

AU - Chen, Chia Yen

AU - Churchhouse, Claire

AU - Corvin, Aiden P.

AU - Craddock, Nicholas

AU - Curtis, David

AU - Di Florio, Arianna

AU - Dickerson, Faith

AU - Freimer, Nelson B.

AU - Goes, Fernando S.

AU - Jia, Xiaoming

AU - Jones, Ian

AU - Jones, Lisa

AU - Jonsson, Lina

AU - Kahn, Rene S.

AU - Landén, Mikael

AU - Locke, Adam E.

AU - McIntosh, Andrew M.

AU - McQuillin, Andrew

AU - Morris, Derek W.

AU - O’Donovan, Michael C.

AU - Ophoff, Roel A.

AU - Owen, Michael J.

AU - Pedersen, Nancy L.

AU - Posthuma, Danielle

AU - Reif, Andreas

AU - Risch, Neil

AU - Schaefer, Catherine

AU - Scott, Laura

AU - Singh, Tarjinder

AU - Smoller, Jordan W.

AU - Solomonson, Matthew

AU - Clair, David St

AU - Stahl, Eli A.

AU - Vreeker, Annabel

AU - Walters, James T.R.

AU - Wang, Weiqing

AU - Watts, Nicholas A.

AU - Yolken, Robert

AU - Zandi, Peter P.

AU - Neale, Benjamin M.

PY - 2022/5

Y1 - 2022/5

N2 - 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.

AB - 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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JO - Nature genetics

JF - Nature genetics

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ER -

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

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