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

Eli A. Stahl (Corresponding Author), 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 & 33 others 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, David St Clair, eQTLGen Consortium, BIOS Consortium, the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)793-803
Number of pages11
JournalNature Genetics
Volume51
DOIs
Publication statusPublished - 1 May 2019

Fingerprint

Genome-Wide Association Study
Bipolar Disorder
Genome
Neurotransmitter Transport Proteins
Endocannabinoids
Genetic Heterogeneity
Major Depressive Disorder
Ion Channels
Psychotic Disorders
Genes
Psychiatry
Schizophrenia
Insulin

Keywords

  • Bipolar disorder
  • genomes

ASJC Scopus subject areas

  • Genetics

Cite this

Stahl, E. A., Breen, G., Forstner, A. J., McQuillin, A., Ripke, S., Trubetskoy, V., ... the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium (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

Genome-wide association study identifies 30 loci associated with bipolar disorder. / Stahl, Eli A. (Corresponding Author); Breen, Gerome; Forstner, Andreas J.; McQuillin, Andrew; Ripke, Stephan; Trubetskoy, Vassily; Mattheisen, Manuel; Wang, Yunpeng; Coleman, Jonathan R.I.; Gaspar, Héléna A.; de Leeuw, Christiaan A.; Steinberg, Stacy; Pavlides, Jennifer M.Whitehead; Trzaskowski, Maciej; Byrne, Enda M.; Pers, Tune H.; Holmans, Peter A.; Richards, Alexander L.; Abbott, Liam; Agerbo, Esben; Akil, Huda; Albani, Diego; Alliey-Rodriguez, Ney; Als, Thomas D.; Anjorin, Adebayo; Antilla, Verneri; Awasthi, Swapnil; Badner, Judith A.; Bækvad-Hansen, Marie; Barchas, Jack D.; Bass, Nicholas; Bauer, Michael; Belliveau, Richard; Bergen, Sarah E.; Pedersen, Carsten Bøcker; Bøen, Erlend; Boks, Marco P.; Boocock, James; Budde, Monika; Bunney, William; Burmeister, Margit; Bybjerg-Grauholm, Jonas; Byerley, William; Casas, Miquel; Cerrato, Felecia; Cervantes, Pablo; Chambert, Kimberly; Charney, Alexander W.; Chen, Danfeng; St Clair, David; eQTLGen Consortium; BIOS Consortium; the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium.

In: Nature Genetics, Vol. 51, 01.05.2019, p. 793-803.

Research output: Contribution to journalArticle

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, St Clair, D, eQTLGen Consortium, BIOS Consortium & the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium 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
Stahl EA, Breen G, Forstner AJ, McQuillin A, Ripke S, Trubetskoy V et al. Genome-wide association study identifies 30 loci associated with bipolar disorder. Nature Genetics. 2019 May 1;51:793-803. https://doi.org/10.1038/s41588-019-0397-8
Stahl, Eli A. ; Breen, Gerome ; Forstner, Andreas J. ; McQuillin, Andrew ; Ripke, Stephan ; Trubetskoy, Vassily ; Mattheisen, Manuel ; Wang, Yunpeng ; Coleman, Jonathan R.I. ; Gaspar, Héléna A. ; de Leeuw, Christiaan A. ; Steinberg, Stacy ; Pavlides, Jennifer M.Whitehead ; Trzaskowski, Maciej ; Byrne, Enda M. ; Pers, Tune H. ; Holmans, Peter A. ; Richards, Alexander L. ; Abbott, Liam ; Agerbo, Esben ; Akil, Huda ; Albani, Diego ; Alliey-Rodriguez, Ney ; Als, Thomas D. ; Anjorin, Adebayo ; Antilla, Verneri ; Awasthi, Swapnil ; Badner, Judith A. ; Bækvad-Hansen, Marie ; Barchas, Jack D. ; Bass, Nicholas ; Bauer, Michael ; Belliveau, Richard ; Bergen, Sarah E. ; Pedersen, Carsten Bøcker ; Bøen, Erlend ; Boks, Marco P. ; Boocock, James ; Budde, Monika ; Bunney, William ; Burmeister, Margit ; Bybjerg-Grauholm, Jonas ; Byerley, William ; Casas, Miquel ; Cerrato, Felecia ; Cervantes, Pablo ; Chambert, Kimberly ; Charney, Alexander W. ; Chen, Danfeng ; St Clair, David ; eQTLGen Consortium ; BIOS Consortium ; the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium. / Genome-wide association study identifies 30 loci associated with bipolar disorder. In: Nature Genetics. 2019 ; Vol. 51. pp. 793-803.
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abstract = "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.",
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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.

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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 - St Clair, David

AU - eQTLGen Consortium

AU - BIOS Consortium

AU - the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

N1 - This paper is dedicated to the memory of Psychiatric Genomics Consortium (PGC) founding member and Bipolar Disorder Working Group co-chair Pamela Sklar. We thank the participants who donated their time, experiences and DNA to this research, and the clinical and scientific teams that worked with them. We are deeply indebted to the investigators who comprise the PGC. Analyses were carried out on the NL Genetic Cluster Computer (http://www.geneticcluster.org), hosted by SURFsara, and the Mount Sinai high performance computing cluster (http://hpc.mssm.edu). PGC members have received major funding from the US National Institute of Mental Health. This work was funded in part by the Brain and Behavior Research Foundation, Stanley Medical Research Institute, University of Michigan, Pritzker Neuropsychiatric Disorders Research Fund L.L.C., Marriot Foundation and the Mayo Clinic Center for Individualized Medicine, the NIMH Intramural Research Program; Canadian Institutes of Health Research; the UK Maudsley NHS Foundation Trust, NIHR, NRS, MRC, Wellcome Trust; European Research Council; German Ministry for Education and Research, German Research Foundation IZKF of Münster, Deutsche Forschungsgemeinschaft, ImmunoSensation, the Dr Lisa-Oehler Foundation, University of Bonn; the Swiss National Science Foundation; French Foundation FondaMental and ANR; Spanish Ministerio de Economía, CIBERSAM, Industria y Competitividad, European Regional Development Fund (ERDF), Generalitat de Catalunya, EU Horizon 2020 Research and Innovation Programme; BBMRI-NL; South-East Norway Regional Health Authority and Mrs Throne-Holst; Swedish Research Council, Stockholm County Council, Söderström Foundation; Lundbeck Foundation, Aarhus University; Australia NHMRC, NSW Ministry of Health, Janette M. O’Neil and Betty C. Lynch. The views expressed are those of the authors and not necessarily those of their institutions or any funding or regulatory bodies. Additional acknowledgements, including funding sources, are presented in the Supplementary Note.

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

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