Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

HUNT All-In Psychiatry

doi:10.1038/s41588-021-00857-4

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

HUNT All-In Psychiatry

Molecular Biosciences

Icahn School of Medicine at Mount Sinai
University Hospital Bonn
ICS-6/Structural Biochemistry
Philipps-University
Oslo University Hospital
University of Oslo
Mayo Clinic
King's College London
University of Queensland
Aarhus University
The Lundbeck Foundation Initiative for Integrative Psychiatric Research
SUNY Downstate Medical Center
James J. Peters VA Medical Center
Norwegian University of Science and Technology (NTNU)
Karolinska Institutet
Trondheim University Hospital
University of California
Fujita Health University School of Medicine
Broad Institute
Harvard Medical School
University of Tartu
Charité – Universitätsmedizin Berlin
deCODE genetics
Sungkyunkwan University
Mental Health Research Center
Ludwig-Maximilians-University
University College London
Department of Neuroscience
University of Chicago
Northwestern University
Berkshire Healthcare NHS Foundation Trust
Massachusetts General Hospital
University of Athens
Sungkyunkwan University
Statens Serum Institut
University Hospital Carl Gustav Carus
Medical University of Graz
Diakonhjemmet Hospital
University Medical Centre Utrecht
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM)
Hospital Universitari Vall d'Hebron
Autonomous University of Barcelona (UAB)
University Hospital Frankfurt
University of California San Francisco
University of Newcastle
McGill University
University of Edinburgh
Max Planck Institute of Psychiatry
Universidad Autonoma de Nuevo Leon
Queen Mary University of London
Poznan University of Medical Sciences
University of California San Diego
University Clinics
University of Bergen
Cardiff University
Newcastle University
Indiana University-Purdue University Indianapolis
Heidelberg University
University Medical Centre Göttingen
Dalhousie University, Faculty of Medicine
Yale University School of Medicine
VA Connecticut Health System
University of Missouri
QIMR Berghofer Medical Research Institute
University of Worcester
University Regional Hospital
Seoul National University College of Medicine
Landspitali - The National University Hospital of Iceland
University of Tübingen
University of Basel
University Hospital Basel
“Translationnal Psychiatry”
UMR-S955
International Max Planck Research School for Translational Psychiatry
University of Tokyo
RIKEN Center for Integrative Medical Sciences
Centre for Addiction and Mental Health
University of Toronto
University of Toronto Faculty of Medicine
University of Würzburg
SUNY Downstate Medical Center
Barcelona Institute for Global Health
School of Health Sciences
University of Pennsylvania Perelman School of Medicine
Altrecht
GGZ inGeest
VU University Medical Center
Erasmus MC
Karolinska University Hospital
North East London NHS Foundation Trust
University Hospital Cologne
Korea University College of Medicine
HudsonAlpha Institute for Biotechnology
McGill University
McGill University
University of Edinburgh
University of Bonn
University of Athens
Stellenbosch University
Intl. Agency for Research on Cancer
University of Sarajevo Medical Faculty
The Johns Hopkins University School of Medicine
Warneford Hospital
University of Oxford Medical Sciences Division
Emory University School of Medicine
Washington University School of Medicine in St. Louis
University of Granada
Sport and Health University Research Institute (iMUDS)
Vanderbilt University Medical Center
University of Barcelona
University of Iceland
University of Glasgow, G11 6NT
University of Southern California
PsyQ
University of Cape Town
Nofer Institute of Occupational Medicine
Neuroscience Research Australia
University of New South Wales
Universidad Autónoma de Madrid
University of California
Psychiatrisches Zentrum
Pfizer Global Research and Development
Bethlem Royal Hospital
Umeå University
National Institute of Mental Health
Pirogov Russian National Research Medical University (RNRMU)
University of Münster
Melbourne Medical School
University of Melbourne
Université Paris Descartes-Sorbonne Paris Cité
Mondor University Hospitals
University of Pennsylvania
University of Michigan School of Public Health
CGPM
University of New South Wales Faculty of Medicine, School of Psychiatry
Trinity College Dublin
Eginition Hospital
Boston Children's Hospital
Alexandru Obregia Clinical Psychiatric Hospital
The University of Western Australia
University of Gothenburg
LLC
M. Sklodowska-Curie Memorial Cancer Center and Institute of Oncology
University of Florida
Lindner Center of HOPE
National Institute of Mental Health Intramural Research Program
Aarhus University Hospital
Munich Cluster for Systems Neurology (SyNergy)
University of Liverpool
VA San Diego Healthcare System
University of Copenhagen
Haukeland University Hospital
College of Medicine and Health Sciences United Arab Emirates University
University of the United Arab Emirates
Vrije Universiteit Amsterdam
Amsterdam Neuroscience
SUNY Upstate Medical University
University of Bologna
Hospital Namsos
University of North Carolina
McGill University
Emory University
Copenhagen University Hospital
Indiana University School of Medicine
McGill University

Research output: Contribution to a Journal (Peer & Non Peer) › Article › peer-review

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Abstract

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

Original language	English
Pages (from-to)	817-829
Number of pages	13
Journal	Nature Genetics
Volume	53
Issue number	6
DOIs	https://doi.org/10.1038/s41588-021-00857-4
Publication status	Published - Jun 2021

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10.1038/s41588-021-00857-4

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@article{469f9d5110ae4e2cbfea08ae3874c2a4,

title = "Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology",

abstract = "Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.",

author = "\{HUNT All-In Psychiatry\} and Niamh Mullins and Forstner, \{Andreas J.\} and O{\textquoteright}Connell, \{Kevin S.\} and Brandon Coombes and Coleman, \{Jonathan R.I.\} and Zhen Qiao and Als, \{Thomas D.\} and Bigdeli, \{Tim B.\} and Sigrid B{\o}rte and Julien Bryois and Charney, \{Alexander W.\} and Drange, \{Ole Kristian\} and Gandal, \{Michael J.\} and Hagenaars, \{Saskia P.\} and Masashi Ikeda and Nolan Kamitaki and Minsoo Kim and Kristi Krebs and Georgia Panagiotaropoulou and Schilder, \{Brian M.\} and Sloofman, \{Laura G.\} and Stacy Steinberg and Vassily Trubetskoy and Winsvold, \{Bendik S.\} and Won, \{Hong Hee\} and Liliya Abramova and Kristina Adorjan and Esben Agerbo and \{Al Eissa\}, Mariam and Diego Albani and Ney Alliey-Rodriguez and Adebayo Anjorin and Verneri Antilla and Anastasia Antoniou and Swapnil Awasthi and Baek, \{Ji Hyun\} and Marie B{\ae}kvad-Hansen and Nicholas Bass and Michael Bauer and Beins, \{Eva C.\} and Bergen, \{Sarah E.\} and Armin Birner and \{B{\o}cker Pedersen\}, Carsten and Erlend B{\o}en and Boks, \{Marco P.\} and Rosa Bosch and Murielle Brum and Brumpton, \{Ben M.\} and Nathalie Brunkhorst-Kanaan and Monika Budde and Jonas Bybjerg-Grauholm and William Byerley and Murray Cairns and Miquel Casas and Pablo Cervantes and Clarke, \{Toni Kim\} and Cristiana Cruceanu and Alfredo Cuellar-Barboza and Julie Cunningham and David Curtis and Czerski, \{Piotr M.\} and Dale, \{Anders M.\} and Nina Dalkner and David, \{Friederike S.\} and Franziska Degenhardt and Srdjan Djurovic and Dobbyn, \{Amanda L.\} and Athanassios Douzenis and Torbj{\o}rn Elvs{\aa}shagen and Valentina Escott-Price and Ferrier, \{I. Nicol\} and Alessia Fiorentino and Foroud, \{Tatiana M.\} and Liz Forty and Josef Frank and Oleksandr Frei and Freimer, \{Nelson B.\} and Louise Fris{\'e}n and Katrin Gade and Julie Garnham and Joel Gelernter and \{Gi{\o}rtz Pedersen\}, Marianne and Gizer, \{Ian R.\} and Gordon, \{Scott D.\} and Katherine Gordon-Smith and Greenwood, \{Tiffany A.\} and Jakob Grove and Jos{\'e} Guzman-Parra and Kyooseob Ha and Magnus Haraldsson and Martin Hautzinger and Urs Heilbronner and Dennis Hellgren and Stefan Herms and Per Hoffmann and Holmans, \{Peter A.\} and Laura Huckins and St{\'e}phane Jamain and Johnson, \{Jessica S.\} and Morris, \{Derek W.\}",

note = "Publisher Copyright: {\textcopyright} 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.",

year = "2021",

month = jun,

doi = "10.1038/s41588-021-00857-4",

language = "English",

volume = "53",

pages = "817--829",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Research",

number = "6",

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TY - JOUR

T1 - Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

AU - HUNT All-In Psychiatry

AU - Mullins, Niamh

AU - Forstner, Andreas J.

AU - O’Connell, Kevin S.

AU - Coombes, Brandon

AU - Coleman, Jonathan R.I.

AU - Qiao, Zhen

AU - Als, Thomas D.

AU - Bigdeli, Tim B.

AU - Børte, Sigrid

AU - Bryois, Julien

AU - Charney, Alexander W.

AU - Drange, Ole Kristian

AU - Gandal, Michael J.

AU - Hagenaars, Saskia P.

AU - Ikeda, Masashi

AU - Kamitaki, Nolan

AU - Kim, Minsoo

AU - Krebs, Kristi

AU - Panagiotaropoulou, Georgia

AU - Schilder, Brian M.

AU - Sloofman, Laura G.

AU - Steinberg, Stacy

AU - Trubetskoy, Vassily

AU - Winsvold, Bendik S.

AU - Won, Hong Hee

AU - Abramova, Liliya

AU - Adorjan, Kristina

AU - Agerbo, Esben

AU - Al Eissa, Mariam

AU - Albani, Diego

AU - Alliey-Rodriguez, Ney

AU - Anjorin, Adebayo

AU - Antilla, Verneri

AU - Antoniou, Anastasia

AU - Awasthi, Swapnil

AU - Baek, Ji Hyun

AU - Bækvad-Hansen, Marie

AU - Bass, Nicholas

AU - Bauer, Michael

AU - Beins, Eva C.

AU - Bergen, Sarah E.

AU - Birner, Armin

AU - Bøcker Pedersen, Carsten

AU - Bøen, Erlend

AU - Boks, Marco P.

AU - Bosch, Rosa

AU - Brum, Murielle

AU - Brumpton, Ben M.

AU - Brunkhorst-Kanaan, Nathalie

AU - Budde, Monika

AU - Bybjerg-Grauholm, Jonas

AU - Byerley, William

AU - Cairns, Murray

AU - Casas, Miquel

AU - Cervantes, Pablo

AU - Clarke, Toni Kim

AU - Cruceanu, Cristiana

AU - Cuellar-Barboza, Alfredo

AU - Cunningham, Julie

AU - Curtis, David

AU - Czerski, Piotr M.

AU - Dale, Anders M.

AU - Dalkner, Nina

AU - David, Friederike S.

AU - Degenhardt, Franziska

AU - Djurovic, Srdjan

AU - Dobbyn, Amanda L.

AU - Douzenis, Athanassios

AU - Elvsåshagen, Torbjørn

AU - Escott-Price, Valentina

AU - Ferrier, I. Nicol

AU - Fiorentino, Alessia

AU - Foroud, Tatiana M.

AU - Forty, Liz

AU - Frank, Josef

AU - Frei, Oleksandr

AU - Freimer, Nelson B.

AU - Frisén, Louise

AU - Gade, Katrin

AU - Garnham, Julie

AU - Gelernter, Joel

AU - Giørtz Pedersen, Marianne

AU - Gizer, Ian R.

AU - Gordon, Scott D.

AU - Gordon-Smith, Katherine

AU - Greenwood, Tiffany A.

AU - Grove, Jakob

AU - Guzman-Parra, José

AU - Ha, Kyooseob

AU - Haraldsson, Magnus

AU - Hautzinger, Martin

AU - Heilbronner, Urs

AU - Hellgren, Dennis

AU - Herms, Stefan

AU - Hoffmann, Per

AU - Holmans, Peter A.

AU - Huckins, Laura

AU - Jamain, Stéphane

AU - Johnson, Jessica S.

AU - Morris, Derek W.

PY - 2021/6

Y1 - 2021/6

N2 - Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

AB - Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

UR - https://www.scopus.com/pages/publications/85107422437

U2 - 10.1038/s41588-021-00857-4

DO - 10.1038/s41588-021-00857-4

M3 - Article

SN - 1061-4036

VL - 53

SP - 817

EP - 829

JO - Nature Genetics

JF - Nature Genetics

IS - 6

ER -

Genome-wide association study of more than 40,000 bipolar disorder cases provides new insights into the underlying biology

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