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

eQTLGen Consortium; BIOS Consortium; the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

doi:10.1038/s41588-019-0397-8

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

eQTLGen Consortium, BIOS Consortium, the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium

Research output: Contribution to Journal › Article › Academic › peer-review

226 Downloads (Pure)

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
DOIs	https://doi.org/10.1038/s41588-019-0397-8
Publication status	Published - 1 May 2019

Funding

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. T.E.T., S. Steinberg, H.S. and K.S. are employed by deCODE Genetics/Amgen. Multiple additional authors work for pharmaceutical or biotechnology companies in a manner directly analogous to academic co-authors and collaborators. A.H.Y. has given paid lectures and is on advisory boards for the following companies with drugs used in affective and related disorders: Astra Zeneca, Eli Lilly, Janssen, Lundbeck, Sunovion, Servier, Livanova. A.H.Y. is Lead Investigator for Embolden Study (Astra Zeneca), BCI Neuroplasticity Study and Aripiprazole Mania Study, which are investigator-initiated studies from Astra Zeneca, Eli Lilly, Lundbeck and Wyeth. J.N. is an investigator for Janssen. P.F.S. reports the following potentially competing interests: Lundbeck (advisory committee), Pfizer (Scientific Advisory Board member) and Roche (grant recipient, speaker reimbursement). G.B. reports consultancy and speaker fees from Eli Lilly and Illumina and grant funding from Eli Lilly. O.A.A. has received speaker fees from Lundbeck. J.A.R.-Q. was on the speakers’ bureau and/or acted as consultant for Eli Lilly, Janssen-Cilag, Novartis, Shire, Lundbeck, Almirall, Braingaze, Sincrolab and Rubió in the last 5 years. He also received travel awards (air tickets and hotel) for taking part in psychiatric meetings from Janssen-Cilag, Rubió, Shire and Eli Lilly. The Department of Psychiatry chaired by him received unrestricted educational and research support from the following companies in the last 5 years: Eli Lilly, Lundbeck, Janssen-Cilag, Actelion, Shire, Ferrer, Oryzon, Roche, Psious and Rubió. E.V. has received grants and served as consultant, advisor or CME speaker for the following entities: AB-Biotics, Abbott, Allergan, Angelini, Astra Zeneca, Bristol-Myers Squibb, Dainippon Sumitomo Pharma, Farmindustria, Ferrer, Forest Research Institute, Gedeon Richter, Glaxo-Smith-Kline, Janssen, Lundbeck, Otsuka, Pfizer, Roche, SAGE, Sanofi-Aventis, Servier, Shire, Sunovion, Takeda, the Brain and Behaviour Foundation, the Catalan Government (AGAUR and PERIS), the Spanish Ministry of Science, Innovation, and Universities (AES and CIBERSAM), the Seventh European Framework Programme and Horizon 2020 and the Stanley Medical Research Institute. T. Elvsåshagen has received speaker fees from Lundbeck. All other authors declare no competing interests.

Funders	Funder number
BBMRI-NL
CIBERSAM, Industria y Competitividad
Dr Lisa-Oehler Foundation
French Foundation FondaMental
German Research Foundation IZKF
South-East Norway Regional Health Authority and Mrs Throne-Holst
Spanish Ministerio de Economía
Söderström Foundation
UK Maudsley NHS Foundation Trust
National Institute of Mental Health	U01MH109514
Mayo Clinic
Brain and Behavior Research Foundation
National Rosacea Society
National Institute on Handicapped Research
Stanley Medical Research Institute
University of Michigan
Wellcome Trust
J. Willard and Alice S. Marriott Foundation
Virginia Marine Resources Commission
Canadian Institutes of Health Research
European Research Council
National Health and Medical Research Council
Deutsche Forschungsgemeinschaft
Agence Nationale de la Recherche
Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung
Bundesministerium für Bildung und Forschung
Generalitat de Catalunya
Lundbeckfonden
Stockholms Läns Landsting
Vetenskapsrådet
Horizon 2020
Rheinische Friedrich-Wilhelms-Universität Bonn
European Regional Development Fund
NSW Ministry of Health

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/s41588-019-0397-8

Genome-wide association study identifies 30 loci associated with bipolar disorderFinal published version, 1.97 MBLicence: Article 25fa Dutch Copyright Act

Persistent URL (handle)

Persistent link

Cite this

@article{452090bc794e4caea065479ffc802a17,

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. ",

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 and Radhika Kandaswamy and Robert Karlsson and Kennedy, {James L.} and Sarah Kittel-Schneider and Knowles, {James A.} and Manolis Kogevinas and Koller, {Anna C.} and Ralph Kupka and Catharina Lavebratt and Jacob Lawrence and Lawson, {William B.} and Markus Leber and Lee, {Phil H.} and Levy, {Shawn E.} and Li, {Jun Z.} and Chunyu Liu and Susanne Lucae and Anna Maaser and MacIntyre, {Donald J.} and Mahon, {Pamela B.} and Wolfgang Maier and Lina Martinsson and Steve McCarroll and Peter McGuffin and McInnis, {Melvin G.} and McKay, {James D.} and Helena Medeiros and Medland, {Sarah E.} and Fan Meng and Lili Milani and Montgomery, {Grant W.} and Morris, {Derek W.} and M{\"u}hleisen, {Thomas W.} and Niamh Mullins and Hoang Nguyen and Nievergelt, {Caroline M.} and Adolfsson, {Annelie Nordin} and Nwulia, {Evaristus A.} and Claire O{\textquoteright}Donovan and Loohuis, {Loes M.Olde} and Ori, {Anil P.S.} and Lilijana Oruc and Urban {\"O}sby and Perlis, {Roy H.} and Amy Perry and Andrea Pfennig and Potash, {James B.} and Purcell, {Shaun M.} and Regeer, {Eline J.} and Andreas Reif and Reinbold, {C{\'e}line S.} and Rice, {John P.} and Fabio Rivas and Margarita Rivera and Panos Roussos and Ruderfer, {Douglas M.} and Euijung Ryu and Cristina S{\'a}nchez-Mora and Schatzberg, {Alan F.} and Scheftner, {William A.} and Schork, {Nicholas J.} and {Shannon Weickert}, Cynthia and Tatyana Shehktman and Shilling, {Paul D.} and Engilbert Sigurdsson and Claire Slaney and Smeland, {Olav B.} and Sobell, {Janet L.} and {S{\o}holm Hansen}, Christine and Spijker, {Anne T.} and {St Clair}, David and Michael Steffens and Strauss, {John S.} and Fabian Streit and Jana Strohmaier and Szabolcs Szelinger and Thompson, {Robert C.} and Thorgeirsson, {Thorgeir E.} and Jens Treutlein and Helmut Vedder and Weiqing Wang and Watson, {Stanley J.} and Weickert, {Thomas W.} and Witt, {Stephanie H.} and Simon Xi and Wei Xu and Young, {Allan H.} and Peter Zandi and Peng Zhang and Sebastian Z{\"o}llner and Rolf Adolfsson and Ingrid Agartz and Martin Alda and Lena Backlund and Baune, {Bernhard T.} and Frank Bellivier and Berrettini, {Wade H.} and Biernacka, {Joanna M.} and Blackwood, {Douglas H.R.} and Michael Boehnke and B{\o}rglum, {Anders D.} and Aiden Corvin and Nicholas Craddock and Daly, {Mark J.} and Udo Dannlowski and T{\~o}nu Esko and Bruno Etain and Mark Frye and Fullerton, {Janice M.} and Gershon, {Elliot S.} and Michael Gill and Fernando Goes and Maria Grigoroiu-Serbanescu and Joanna Hauser and Hougaard, {David M.} and Hultman, {Christina M.} and Ian Jones and Jones, {Lisa A.} and Kahn, {Ren{\'e} S.} and George Kirov and Mikael Land{\'e}n and Marion Leboyer and Lewis, {Cathryn M.} and Li, {Qingqin S.} and Jolanta Lissowska and Martin, {Nicholas G.} and Fermin Mayoral and McElroy, {Susan L.} and McIntosh, {Andrew M.} and McMahon, {Francis J.} and Ingrid Melle and Andres Metspalu and Mitchell, {Philip B.} and Gunnar Morken and Ole Mors and Mortensen, {Preben Bo} and Bertram M{\"u}ller-Myhsok and Myers, {Richard M.} and Neale, {Benjamin M.} and Vishwajit Nimgaonkar and Merete Nordentoft and N{\"o}then, {Markus M.} and O{\textquoteright}Donovan, {Michael C.} and Oedegaard, {Ketil J.} and Owen, {Michael J.} and Paciga, {Sara A.} and Carlos Pato and Pato, {Michele T.} and Danielle Posthuma and Ramos-Quiroga, {Josep Antoni} and Marta Ribas{\'e}s and Marcella Rietschel and Rouleau, {Guy A.} and Martin Schalling and Schofield, {Peter R.} and Schulze, {Thomas G.} and Alessandro Serretti and Smoller, {Jordan W.} and Hreinn Stefansson and Kari Stefansson and Eystein Stordal and Sullivan, {Patrick F.} and Gustavo Turecki and Vaaler, {Arne E.} and Eduard Vieta and Vincent, {John B.} and Thomas Werge and Nurnberger, {John I.} and Wray, {Naomi R.} and {Di Florio}, Arianna and Edenberg, {Howard J.} and Sven Cichon and Ophoff, {Roel A.} and Scott, {Laura J.} and Andreassen, {Ole A.} and John Kelsoe and Pamela Sklar and {eQTLGen Consortium} and {BIOS Consortium} and {the Bipolar Disorder Working Group of the Psychiatric Genomics Consortium}",

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",

publisher = "Nature Publishing Group",

number = "5",

}

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

AU - Kandaswamy, Radhika

AU - Karlsson, Robert

AU - Kennedy, James L.

AU - Kittel-Schneider, Sarah

AU - Knowles, James A.

AU - Kogevinas, Manolis

AU - Koller, Anna C.

AU - Kupka, Ralph

AU - Lavebratt, Catharina

AU - Lawrence, Jacob

AU - Lawson, William B.

AU - Leber, Markus

AU - Lee, Phil H.

AU - Levy, Shawn E.

AU - Li, Jun Z.

AU - Liu, Chunyu

AU - Lucae, Susanne

AU - Maaser, Anna

AU - MacIntyre, Donald J.

AU - Mahon, Pamela B.

AU - Maier, Wolfgang

AU - Martinsson, Lina

AU - McCarroll, Steve

AU - McGuffin, Peter

AU - McInnis, Melvin G.

AU - McKay, James D.

AU - Medeiros, Helena

AU - Medland, Sarah E.

AU - Meng, Fan

AU - Milani, Lili

AU - Montgomery, Grant W.

AU - Morris, Derek W.

AU - Mühleisen, Thomas W.

AU - Mullins, Niamh

AU - Nguyen, Hoang

AU - Nievergelt, Caroline M.

AU - Adolfsson, Annelie Nordin

AU - Nwulia, Evaristus A.

AU - O’Donovan, Claire

AU - Loohuis, Loes M.Olde

AU - Ori, Anil P.S.

AU - Oruc, Lilijana

AU - Ösby, Urban

AU - Perlis, Roy H.

AU - Perry, Amy

AU - Pfennig, Andrea

AU - Potash, James B.

AU - Purcell, Shaun M.

AU - Regeer, Eline J.

AU - Reif, Andreas

AU - Reinbold, Céline S.

AU - Rice, John P.

AU - Rivas, Fabio

AU - Rivera, Margarita

AU - Roussos, Panos

AU - Ruderfer, Douglas M.

AU - Ryu, Euijung

AU - Sánchez-Mora, Cristina

AU - Schatzberg, Alan F.

AU - Scheftner, William A.

AU - Schork, Nicholas J.

AU - Shannon Weickert, Cynthia

AU - Shehktman, Tatyana

AU - Shilling, Paul D.

AU - Sigurdsson, Engilbert

AU - Slaney, Claire

AU - Smeland, Olav B.

AU - Sobell, Janet L.

AU - Søholm Hansen, Christine

AU - Spijker, Anne T.

AU - St Clair, David

AU - Steffens, Michael

AU - Strauss, John S.

AU - Streit, Fabian

AU - Strohmaier, Jana

AU - Szelinger, Szabolcs

AU - Thompson, Robert C.

AU - Thorgeirsson, Thorgeir E.

AU - Treutlein, Jens

AU - Vedder, Helmut

AU - Wang, Weiqing

AU - Watson, Stanley J.

AU - Weickert, Thomas W.

AU - Witt, Stephanie H.

AU - Xi, Simon

AU - Xu, Wei

AU - Young, Allan H.

AU - Zandi, Peter

AU - Zhang, Peng

AU - Zöllner, Sebastian

AU - Adolfsson, Rolf

AU - Agartz, Ingrid

AU - Alda, Martin

AU - Backlund, Lena

AU - Baune, Bernhard T.

AU - Bellivier, Frank

AU - Berrettini, Wade H.

AU - Biernacka, Joanna M.

AU - Blackwood, Douglas H.R.

AU - Boehnke, Michael

AU - Børglum, Anders D.

AU - Corvin, Aiden

AU - Craddock, Nicholas

AU - Daly, Mark J.

AU - Dannlowski, Udo

AU - Esko, Tõnu

AU - Etain, Bruno

AU - Frye, Mark

AU - Fullerton, Janice M.

AU - Gershon, Elliot S.

AU - Gill, Michael

AU - Goes, Fernando

AU - Grigoroiu-Serbanescu, Maria

AU - Hauser, Joanna

AU - Hougaard, David M.

AU - Hultman, Christina M.

AU - Jones, Ian

AU - Jones, Lisa A.

AU - Kahn, René S.

AU - Kirov, George

AU - Landén, Mikael

AU - Leboyer, Marion

AU - Lewis, Cathryn M.

AU - Li, Qingqin S.

AU - Lissowska, Jolanta

AU - Martin, Nicholas G.

AU - Mayoral, Fermin

AU - McElroy, Susan L.

AU - McIntosh, Andrew M.

AU - McMahon, Francis J.

AU - Melle, Ingrid

AU - Metspalu, Andres

AU - Mitchell, Philip B.

AU - Morken, Gunnar

AU - Mors, Ole

AU - Mortensen, Preben Bo

AU - Müller-Myhsok, Bertram

AU - Myers, Richard M.

AU - Neale, Benjamin M.

AU - Nimgaonkar, Vishwajit

AU - Nordentoft, Merete

AU - Nöthen, Markus M.

AU - O’Donovan, Michael C.

AU - Oedegaard, Ketil J.

AU - Owen, Michael J.

AU - Paciga, Sara A.

AU - Pato, Carlos

AU - Pato, Michele T.

AU - Posthuma, Danielle

AU - Ramos-Quiroga, Josep Antoni

AU - Ribasés, Marta

AU - Rietschel, Marcella

AU - Rouleau, Guy A.

AU - Schalling, Martin

AU - Schofield, Peter R.

AU - Schulze, Thomas G.

AU - Serretti, Alessandro

AU - Smoller, Jordan W.

AU - Stefansson, Hreinn

AU - Stefansson, Kari

AU - Stordal, Eystein

AU - Sullivan, Patrick F.

AU - Turecki, Gustavo

AU - Vaaler, Arne E.

AU - Vieta, Eduard

AU - Vincent, John B.

AU - Werge, Thomas

AU - Nurnberger, John I.

AU - Wray, Naomi R.

AU - Di Florio, Arianna

AU - Edenberg, Howard J.

AU - Cichon, Sven

AU - Ophoff, Roel A.

AU - Scott, Laura J.

AU - Andreassen, Ole A.

AU - Kelsoe, John

AU - Sklar, Pamela

AU - eQTLGen Consortium

AU - BIOS Consortium

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

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.

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.

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

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

U2 - 10.1038/s41588-019-0397-8

DO - 10.1038/s41588-019-0397-8

M3 - Article

C2 - 31043756

AN - SCOPUS:85065180508

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

Funding

UN SDGs

Access to Document

Persistent URL (handle)

Other files and links

Fingerprint

Cite this