Genome-wide association study identifies 30 loci associated with bipolar disorder

Eli A. Stahl; Gerome Breen; Andreas J. Forstner; Andrew McQuillin; Stephan Ripke; Vassily Trubetskoy; Manuel Mattheisen; Yunpeng Wang; Jonathan R.I. Coleman; Héléna A. Gaspar; Christiaan A. de Leeuw; Stacy Steinberg; Jennifer M.Whitehead Pavlides; Maciej Trzaskowski; Enda M. Byrne; Tune H. Pers; Peter A. Holmans; Alexander L. Richards; Liam Abbott; Esben Agerbo; Huda Akil; Diego Albani; Ney Alliey-Rodriguez; Thomas D. Als; Adebayo Anjorin; Verneri Antilla; Swapnil Awasthi; Judith A. Badner; Marie Bækvad-Hansen; Jack D. Barchas; Nicholas Bass; Michael Bauer; Richard Belliveau; Sarah E. Bergen; Carsten Bøcker Pedersen; Erlend Bøen; Marco P. Boks; James Boocock; Monika Budde; William Bunney; Margit Burmeister; Jonas Bybjerg-Grauholm; William Byerley; Miquel Casas; Felecia Cerrato; Pablo Cervantes; Kimberly Chambert; Alexander W. Charney; Danfeng Chen; Claire Churchhouse; Toni Kim Clarke; William Coryell; David W. Craig; Cristiana Cruceanu; David Curtis; Piotr M. Czerski; Anders M. Dale; Simone de Jong; Franziska Degenhardt; Jurgen Del-Favero; J. Raymond DePaulo; Srdjan Djurovic; Amanda L. Dobbyn; Ashley Dumont; Torbjørn Elvsåshagen; Valentina Escott-Price; Chun Chieh Fan; Sascha B. Fischer; Matthew Flickinger; Tatiana M. Foroud; Liz Forty; Josef Frank; Christine Fraser; Nelson B. Freimer; Louise Frisén; Katrin Gade; Diane Gage; Julie Garnham; Claudia Giambartolomei; Marianne Giørtz Pedersen; Jaqueline Goldstein; Scott D. Gordon; Katherine Gordon-Smith; Elaine K. Green; Melissa J. Green; Tiffany A. Greenwood; Jakob Grove; Weihua Guan; José Guzman-Parra; Marian L. Hamshere; Martin Hautzinger; Urs Heilbronner; Stefan Herms; Maria Hipolito; Per Hoffmann; Dominic Holland; Laura Huckins; Stéphane Jamain; Jessica S. Johnson; Anders Juréus

doi:10.1038/s41588-019-0397-8

Genome-wide association study identifies 30 loci associated with bipolar disorder

Eli A. Stahl, Gerome Breen, Andreas J. Forstner, Andrew McQuillin, Stephan Ripke, Vassily Trubetskoy, Manuel Mattheisen, Yunpeng Wang, Jonathan R.I. Coleman, Héléna A. Gaspar, Christiaan A. de Leeuw, Stacy Steinberg, Jennifer M.Whitehead Pavlides, Maciej Trzaskowski, Enda M. Byrne, Tune H. Pers, Peter A. Holmans, Alexander L. Richards, Liam Abbott, Esben AgerboHuda Akil, Diego Albani, Ney Alliey-Rodriguez, Thomas D. Als, Adebayo Anjorin, Verneri Antilla, Swapnil Awasthi, Judith A. Badner, Marie Bækvad-Hansen, Jack D. Barchas, Nicholas Bass, Michael Bauer, Richard Belliveau, Sarah E. Bergen, Carsten Bøcker Pedersen, Erlend Bøen, Marco P. Boks, James Boocock, Monika Budde, William Bunney, Margit Burmeister, Jonas Bybjerg-Grauholm, William Byerley, Miquel Casas, Felecia Cerrato, Pablo Cervantes, Kimberly Chambert, Alexander W. Charney, Danfeng Chen, Claire Churchhouse, Toni Kim Clarke, William Coryell, David W. Craig, Cristiana Cruceanu, David Curtis, Piotr M. Czerski, Anders M. Dale, Simone de Jong, Franziska Degenhardt, Jurgen Del-Favero, J. Raymond DePaulo, Srdjan Djurovic, Amanda L. Dobbyn, Ashley Dumont, Torbjørn Elvsåshagen, Valentina Escott-Price, Chun Chieh Fan, Sascha B. Fischer, Matthew Flickinger, Tatiana M. Foroud, Liz Forty, Josef Frank, Christine Fraser, Nelson B. Freimer, Louise Frisén, Katrin Gade, Diane Gage, Julie Garnham, Claudia Giambartolomei, Marianne Giørtz Pedersen, Jaqueline Goldstein, Scott D. Gordon, Katherine Gordon-Smith, Elaine K. Green, Melissa J. Green, Tiffany A. Greenwood, Jakob Grove, Weihua Guan, José Guzman-Parra, Marian L. Hamshere, Martin Hautzinger, Urs Heilbronner, Stefan Herms, Maria Hipolito, Per Hoffmann, Dominic Holland, Laura Huckins, Stéphane Jamain, Jessica S. Johnson, Anders Juréus

Department of Psychiatry and Legal Medicine

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Abstract

© 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 −4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 −8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

Original language	English
Pages (from-to)	793-803
Journal	Nature Genetics
Volume	51
DOIs	https://doi.org/10.1038/s41588-019-0397-8
Publication status	Published - 1 May 2019

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10.1038/s41588-019-0397-8

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Stahl, E. A., Breen, G., Forstner, A. J., McQuillin, A., Ripke, S., Trubetskoy, V., Mattheisen, M., Wang, Y., Coleman, J. R. I., Gaspar, H. A., de Leeuw, C. A., Steinberg, S., Pavlides, J. M. W., Trzaskowski, M., Byrne, E. M., Pers, T. H., Holmans, P. A., Richards, A. L., Abbott, L., ... Juréus, A. (2019). Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics, 51, 793-803. https://doi.org/10.1038/s41588-019-0397-8

@article{cf5ab3d0f48e4785889ad1b5e9a23645,

title = "Genome-wide association study identifies 30 loci associated with bipolar disorder",

abstract = "{\textcopyright} 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 −4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 −8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.",

author = "Stahl, {Eli A.} and Gerome Breen and Forstner, {Andreas J.} and Andrew McQuillin and Stephan Ripke and Vassily Trubetskoy and Manuel Mattheisen and Yunpeng Wang and Coleman, {Jonathan R.I.} and Gaspar, {H{\'e}l{\'e}na A.} and {de Leeuw}, {Christiaan A.} and Stacy Steinberg and Pavlides, {Jennifer M.Whitehead} and Maciej Trzaskowski and Byrne, {Enda M.} and Pers, {Tune H.} and Holmans, {Peter A.} and Richards, {Alexander L.} and Liam Abbott and Esben Agerbo and Huda Akil and Diego Albani and Ney Alliey-Rodriguez and Als, {Thomas D.} and Adebayo Anjorin and Verneri Antilla and Swapnil Awasthi and Badner, {Judith A.} and Marie B{\ae}kvad-Hansen and Barchas, {Jack D.} and Nicholas Bass and Michael Bauer and Richard Belliveau and Bergen, {Sarah E.} and Pedersen, {Carsten B{\o}cker} and Erlend B{\o}en and Boks, {Marco P.} and James Boocock and Monika Budde and William Bunney and Margit Burmeister and Jonas Bybjerg-Grauholm and William Byerley and Miquel Casas and Felecia Cerrato and Pablo Cervantes and Kimberly Chambert and Charney, {Alexander W.} and Danfeng Chen and Claire Churchhouse and Clarke, {Toni Kim} and William Coryell and Craig, {David W.} and Cristiana Cruceanu and David Curtis and Czerski, {Piotr M.} and Dale, {Anders M.} and {de Jong}, Simone and Franziska Degenhardt and Jurgen Del-Favero and DePaulo, {J. Raymond} and Srdjan Djurovic and Dobbyn, {Amanda L.} and Ashley Dumont and Torbj{\o}rn Elvs{\aa}shagen and Valentina Escott-Price and Fan, {Chun Chieh} and Fischer, {Sascha B.} and Matthew Flickinger and Foroud, {Tatiana M.} and Liz Forty and Josef Frank and Christine Fraser and Freimer, {Nelson B.} and Louise Fris{\'e}n and Katrin Gade and Diane Gage and Julie Garnham and Claudia Giambartolomei and Pedersen, {Marianne Gi{\o}rtz} and Jaqueline Goldstein and Gordon, {Scott D.} and Katherine Gordon-Smith and Green, {Elaine K.} and Green, {Melissa J.} and Greenwood, {Tiffany A.} and Jakob Grove and Weihua Guan and Jos{\'e} Guzman-Parra and Hamshere, {Marian L.} and Martin Hautzinger and Urs Heilbronner and Stefan Herms and Maria Hipolito and Per Hoffmann and Dominic Holland and Laura Huckins and St{\'e}phane Jamain and Johnson, {Jessica S.} and Anders Jur{\'e}us",

year = "2019",

month = may,

day = "1",

doi = "10.1038/s41588-019-0397-8",

language = "English",

volume = "51",

pages = "793--803",

journal = "Nature Genetics",

issn = "1061-4036",

}

Stahl, EA, Breen, G, Forstner, AJ, McQuillin, A, Ripke, S, Trubetskoy, V, Mattheisen, M, Wang, Y, Coleman, JRI, Gaspar, HA, de Leeuw, CA, Steinberg, S, Pavlides, JMW, Trzaskowski, M, Byrne, EM, Pers, TH, Holmans, PA, Richards, AL, Abbott, L, Agerbo, E, Akil, H, Albani, D, Alliey-Rodriguez, N, Als, TD, Anjorin, A, Antilla, V, Awasthi, S, Badner, JA, Bækvad-Hansen, M, Barchas, JD, Bass, N, Bauer, M, Belliveau, R, Bergen, SE, Pedersen, CB, Bøen, E, Boks, MP, Boocock, J, Budde, M, Bunney, W, Burmeister, M, Bybjerg-Grauholm, J, Byerley, W, Casas, M, Cerrato, F, Cervantes, P, Chambert, K, Charney, AW, Chen, D, Churchhouse, C, Clarke, TK, Coryell, W, Craig, DW, Cruceanu, C, Curtis, D, Czerski, PM, Dale, AM, de Jong, S, Degenhardt, F, Del-Favero, J, DePaulo, JR, Djurovic, S, Dobbyn, AL, Dumont, A, Elvsåshagen, T, Escott-Price, V, Fan, CC, Fischer, SB, Flickinger, M, Foroud, TM, Forty, L, Frank, J, Fraser, C, Freimer, NB, Frisén, L, Gade, K, Gage, D, Garnham, J, Giambartolomei, C, Pedersen, MG, Goldstein, J, Gordon, SD, Gordon-Smith, K, Green, EK, Green, MJ, Greenwood, TA, Grove, J, Guan, W, Guzman-Parra, J, Hamshere, ML, Hautzinger, M, Heilbronner, U, Herms, S, Hipolito, M, Hoffmann, P, Holland, D, Huckins, L, Jamain, S, Johnson, JS & Juréus, A 2019, 'Genome-wide association study identifies 30 loci associated with bipolar disorder', Nature Genetics, vol. 51, pp. 793-803. https://doi.org/10.1038/s41588-019-0397-8

TY - JOUR

T1 - Genome-wide association study identifies 30 loci associated with bipolar disorder

AU - Stahl, Eli A.

AU - Breen, Gerome

AU - Forstner, Andreas J.

AU - McQuillin, Andrew

AU - Ripke, Stephan

AU - Trubetskoy, Vassily

AU - Mattheisen, Manuel

AU - Wang, Yunpeng

AU - Coleman, Jonathan R.I.

AU - Gaspar, Héléna A.

AU - de Leeuw, Christiaan A.

AU - Steinberg, Stacy

AU - Pavlides, Jennifer M.Whitehead

AU - Trzaskowski, Maciej

AU - Byrne, Enda M.

AU - Pers, Tune H.

AU - Holmans, Peter A.

AU - Richards, Alexander L.

AU - Abbott, Liam

AU - Agerbo, Esben

AU - Akil, Huda

AU - Albani, Diego

AU - Alliey-Rodriguez, Ney

AU - Als, Thomas D.

AU - Anjorin, Adebayo

AU - Antilla, Verneri

AU - Awasthi, Swapnil

AU - Badner, Judith A.

AU - Bækvad-Hansen, Marie

AU - Barchas, Jack D.

AU - Bass, Nicholas

AU - Bauer, Michael

AU - Belliveau, Richard

AU - Bergen, Sarah E.

AU - Pedersen, Carsten Bøcker

AU - Bøen, Erlend

AU - Boks, Marco P.

AU - Boocock, James

AU - Budde, Monika

AU - Bunney, William

AU - Burmeister, Margit

AU - Bybjerg-Grauholm, Jonas

AU - Byerley, William

AU - Casas, Miquel

AU - Cerrato, Felecia

AU - Cervantes, Pablo

AU - Chambert, Kimberly

AU - Charney, Alexander W.

AU - Chen, Danfeng

AU - Churchhouse, Claire

AU - Clarke, Toni Kim

AU - Coryell, William

AU - Craig, David W.

AU - Cruceanu, Cristiana

AU - Curtis, David

AU - Czerski, Piotr M.

AU - Dale, Anders M.

AU - de Jong, Simone

AU - Degenhardt, Franziska

AU - Del-Favero, Jurgen

AU - DePaulo, J. Raymond

AU - Djurovic, Srdjan

AU - Dobbyn, Amanda L.

AU - Dumont, Ashley

AU - Elvsåshagen, Torbjørn

AU - Escott-Price, Valentina

AU - Fan, Chun Chieh

AU - Fischer, Sascha B.

AU - Flickinger, Matthew

AU - Foroud, Tatiana M.

AU - Forty, Liz

AU - Frank, Josef

AU - Fraser, Christine

AU - Freimer, Nelson B.

AU - Frisén, Louise

AU - Gade, Katrin

AU - Gage, Diane

AU - Garnham, Julie

AU - Giambartolomei, Claudia

AU - Pedersen, Marianne Giørtz

AU - Goldstein, Jaqueline

AU - Gordon, Scott D.

AU - Gordon-Smith, Katherine

AU - Green, Elaine K.

AU - Green, Melissa J.

AU - Greenwood, Tiffany A.

AU - Grove, Jakob

AU - Guan, Weihua

AU - Guzman-Parra, José

AU - Hamshere, Marian L.

AU - Hautzinger, Martin

AU - Heilbronner, Urs

AU - Herms, Stefan

AU - Hipolito, Maria

AU - Hoffmann, Per

AU - Holland, Dominic

AU - Huckins, Laura

AU - Jamain, Stéphane

AU - Johnson, Jessica S.

AU - Juréus, Anders

PY - 2019/5/1

Y1 - 2019/5/1

N2 - © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 −4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 −8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

AB - © 2019, The Author(s), under exclusive licence to Springer Nature America, Inc. Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study (GWAS) including 20,352 cases and 31,358 controls of European descent, with follow-up analysis of 822 variants with P < 1 × 10 −4 in an additional 9,412 cases and 137,760 controls. Eight of the 19 variants that were genome-wide significant (P < 5 × 10 −8 ) in the discovery GWAS were not genome-wide significant in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis, 30 loci were genome-wide significant, including 20 newly identified loci. The significant loci contain genes encoding ion channels, neurotransmitter transporters and synaptic components. Pathway analysis revealed nine significantly enriched gene sets, including regulation of insulin secretion and endocannabinoid signaling. Bipolar I disorder is strongly genetically correlated with schizophrenia, driven by psychosis, whereas bipolar II disorder is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential biological mechanisms for bipolar disorder.

U2 - 10.1038/s41588-019-0397-8

DO - 10.1038/s41588-019-0397-8

M3 - Article

C2 - 31043756

SN - 1061-4036

VL - 51

SP - 793

EP - 803

JO - Nature Genetics

JF - Nature Genetics

ER -

Genome-wide association study identifies 30 loci associated with bipolar disorder

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