Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

eQTLGen Consortium; 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; Simone de Jong; Radhika Kandaswamy; Peter McGuffin; Niamh Mullins; Allan H Young; Cathryn M Lewis

doi:10.1038/s41588-019-0397-8

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

eQTLGen Consortium, 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 AbbottEsben 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, Simone de Jong, Radhika Kandaswamy, Peter McGuffin, Niamh Mullins, Allan H Young, Cathryn M Lewis

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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.

Original language	English
Pages (from-to)	793-803
Number of pages	11
Journal	Nature Genetics
Volume	51
Issue number	5
Early online date	1 May 2019
DOIs	https://doi.org/10.1038/s41588-019-0397-8
Publication status	Published - May 2019

Keywords

Bipolar Disorder/classification
Case-Control Studies
Depressive Disorder, Major/genetics
Female
Genetic Loci
Genetic Predisposition to Disease
Genome-Wide Association Study
Humans
Male
Polymorphism, Single Nucleotide
Psychotic Disorders/genetics
Schizophrenia/genetics
Systems Biology

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Genome-wide association study_STAHL_Accepted18March2019_GREEN AAMAccepted author manuscript, 694 KB

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eQTLGen Consortium, 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., ... Lewis, C. M. (2019). Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder. Nature Genetics, 51(5), 793-803. https://doi.org/10.1038/s41588-019-0397-8

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title = "Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder",

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.",

keywords = "Bipolar Disorder/classification, Case-Control Studies, Depressive Disorder, Major/genetics, Female, Genetic Loci, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Psychotic Disorders/genetics, Schizophrenia/genetics, Systems Biology",

author = "{eQTLGen Consortium} and 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 {de Jong}, Simone and Radhika Kandaswamy and Peter McGuffin and Niamh Mullins and Young, {Allan H} and Lewis, {Cathryn M}",

year = "2019",

month = may,

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

language = "English",

volume = "51",

pages = "793--803",

journal = "Nature Genetics",

issn = "1061-4036",

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eQTLGen Consortium, 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, de Jong, S, Kandaswamy, R , McGuffin, P , Mullins, N , Young, AH & Lewis, CM 2019, 'Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder', Nature Genetics, vol. 51, no. 5, 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 - eQTLGen Consortium

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 - de Jong, Simone

AU - Kandaswamy, Radhika

AU - McGuffin, Peter

AU - Mullins, Niamh

AU - Young, Allan H

AU - Lewis, Cathryn M

PY - 2019/5

Y1 - 2019/5

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.

AB - 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.

KW - Bipolar Disorder/classification

KW - Case-Control Studies

KW - Depressive Disorder, Major/genetics

KW - Female

KW - Genetic Loci

KW - Genetic Predisposition to Disease

KW - Genome-Wide Association Study

KW - Humans

KW - Male

KW - Polymorphism, Single Nucleotide

KW - Psychotic Disorders/genetics

KW - Schizophrenia/genetics

KW - Systems Biology

UR - http://www.scopus.com/inward/record.url?scp=85065180508&partnerID=8YFLogxK

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

IS - 5

ER -

Genome-wide association study identifies 30 Loci Associated with Bipolar Disorder

Abstract

Keywords

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