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

There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

Abstract

Bipolar disorder is a highly heritable psychiatric disorder. We performed a genome-wide association study 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 (GWS, p < 5×10 ⁻⁸) in the discovery GWAS were not GWS in the combined analysis, consistent with small effect sizes and limited power but also with genetic heterogeneity. In the combined analysis 30 loci were GWS including 20 novel 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. BDI is strongly genetically correlated with schizophrenia, driven by psychosis, whereas BDII is more strongly correlated with major depressive disorder. These findings address key clinical questions and provide potential new biological mechanisms for BD.

Related collections

Most cited references 29

Record: found
Abstract: found
Article: found

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

Cornelius Rietveld, Sarah E. Medland, Jaime Derringer … (2013)

A genome-wide association study (GWAS) of educational attainment was conducted in a discovery sample of 101,069 individuals and a replication sample of 25,490. Three independent single-nucleotide polymorphisms (SNPs) are genome-wide significant (rs9320913, rs11584700, rs4851266), and all three replicate. Estimated effects sizes are small (coefficient of determination R(2) ≈ 0.02%), approximately 1 month of schooling per allele. A linear polygenic score from all measured SNPs accounts for ≈2% of the variance in both educational attainment and cognitive function. Genes in the region of the loci have previously been associated with health, cognitive, and central nervous system phenotypes, and bioinformatics analyses suggest the involvement of the anterior caudate nucleus. These findings provide promising candidate SNPs for follow-up work, and our effect size estimates can anchor power analyses in social-science genetics.

0 comments Cited 300 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013.

Alize J Ferrari, Emily Stockings, Jon-Paul Khoo … (2016)

We present the global burden of bipolar disorder based on findings from the Global Burden of Disease Study 2013 (GBD 2013).

0 comments Cited 166 times – based on 0 reviews      Review now

Bookmark

Record: found
Abstract: found
Article: not found

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Suzanne Sniekers, Sven Stringer, Kyoko Watanabe … (2017)

Intelligence is associated with important economic and health-related life outcomes 1 . Despite substantial heritability 2 (0.54) and confirmed polygenic nature, initial genetic studies were mostly underpowered 3–5 . Here we report a meta-analysis for intelligence of 78,308 individuals. We identify 336 single nucleotide polymorphisms (SNPs) (METAL P 500,000 participants. All participants provided written informed consent; the UK Biobank received ethical approval from the National Research Ethics Service Committee North West–Haydock (reference 11/NW/0382), and all study procedures were performed in accordance with the World Medical Association Declaration of Helsinki ethical principles for medical research. The current study was conducted under the UK Biobank application number 16406. The study design of the UK Biobank has been described in detail elsewhere 35,36 . Briefly, invitation letters were sent out in 2006–2010 to ~9.2 million individuals including all people aged 40–69 years who were registered with the National Health Service and living up to ~25 miles from one of the 22 study assessment centers. A total of 503,325 participants were subsequently recruited into the study 35 . Apart from registry based phenotypic information, extensive self-reported baseline data have been collected by questionnaire, in addition to anthropometric assessments and DNA collection. For the present study we used imputed data obtained from UK Biobank (May 2015 release) including ~73 million genetic variants in 152,249 individuals. Details on the data are provided elsewhere (see URLs). In summary, the first ~50,000 samples were genotyped on the UK BiLEVE Axiom array, and the remaining ~100,000 samples were genotyped on the UK Biobank Axiom array. After standard quality control of the SNPs and samples, which was centrally performed by UK Biobank, the dataset comprised 641,018 autosomal SNPs in 152,256 samples for phasing and imputation. Imputation was performed with a reference panel that included the UK10K haplotype panel and the 1000 Genomes Project Phase 3 reference panel. We used two fluid intelligence phenotypes from the Biobank data set. These are based on questionnaires that were taken either in the assessment center at the initial intake (‘touchscreen’, field 20016) or at a later moment at home (‘web-based’, field 20191). The measures indicate the number of correct answers out of 13 fluid intelligence questions. The data distribution roughly approximates a normal distribution. For the analyses in our study, we only included individuals of Caucasian descent. After removal of related individuals, discordant sex, withdrawn consent, and missing phenotype data, 36,257 individuals remained for analysis for the fluid intelligence touchscreen measure and 28,846 for the web-based version. As 10,984 individuals had taken both the touchscreen and the web-based test, we only included the data from the touchscreen test for these individuals. This resulted in 54,119 individuals with a score on either the fluid intelligence web-based (UKB-wb) or touchscreen (UKB-ts) version (Supplementary Table 1). At the time of taking the test, participants’ ages ranged between 40 and 78. Half of the participants were between 40 and 60 years old, 44% between 60 and 70 and 6% were older than 70. The mean age was 58.98 with a standard deviation of 8.19. Summary statistics from CHIC consortium We downloaded the publicly available combined GWAS results from the meta-analyses as reported by CHIC 5 (see URLs). Details on the included cohorts and performed analyses are reported in the original publication 5 . Briefly, CHIC includes 6 cohorts totaling 12,441 individuals: the Avon Longitudinal Study of Parents and Children (ALSPAC, N = 5,517), the Lothian Birth Cohorts of 1921 and 1936 (LBC1921, N = 464; LBC1936, N = 947), the Brisbane Adolescent Twin Study subsample of Queensland Institute of Medical Research (QIMR, N = 1,752), the Western Australian Pregnancy Cohort Study (Raine, N = 936), and the Twins Early Development Study (TEDS, N = 2,825). All individuals are children aged between 6–18 years. Within each cohort the cognitive performance measure was adjusted for sex and age and principal components were included to adjust for population stratification. See also Supplementary Table 1. Full GWAS data from additional cohorts We used the same additional (non-CHIC) cohorts as described in detail in ref. 7 , which included 11,748 individuals from 5 cohorts. In ref. 7 , results were only reported for 69 SNPs, as these served as a secondary analysis for a look-up effort. In the current study we use the full genome-wide results from these cohorts. GWAS were conducted in 2013 and summary statistics were obtained from the PIs of the 5 cohorts. The quality control protocol entailed excluding SNPs with MAF 0.01. Positional annotations for all lead SNPs and SNPs in LD with the lead SNPs were obtained by performing ANNOVAR gene-based annotation using refSeq genes. In addition, CADD scores 38 , and RegulomeDB 15 scores were annotated to SNPs by matching chromosome, position, reference and alternative alleles. For each SNP eQTLs were extracted from GTEx (44 tissue types) 39 , Blood eQTL browser 40 and BIOS gene-level eQTLs 41 . The eQTLs obtained from GTEx were filtered on gene P-value < 0.05 and eQTLs obtained from the other two databases were filtered on FDR < 0.05. The FDR values were provided by GTEx, BIOS and Blood eQTL browser. For GTEx eQTLs, there is one FDR value available per gene-tissue pair. As such, the FDR is identical for all eQTLs belonging to the same gene-tissue pair. For BIOS and Blood eQTL browser, an FDR value was computed per SNP. To test whether the SNPs were functionally active by means of histone modifications, we obtained epigenetic data from the NIH Roadmap Epigenomics Mapping Consortium 42 and ENCODE 43 . For every 200bp of the genome a 15-core chromatin state was predicted by a Hidden Markov Model based on 5 histone marks (i.e. H3K4me3, H3K4me1, H3K27me3, H3K9me3, and H3K36me3) for 127 tissue/cell types 44 . We annotated chromatin states (15 states in total) to SNPs by matching chromosome and position for every tissue/cell type. We computed the minimum state (1: the most active state) and the consensus state (majority of states) across 127 tissue/cell types for each SNP. Chromatin states were also determined for the 52 genes (47 from the gene-based test + 5 additional genes implicated by single SNP GWAS). For each gene and tissue, the chromatin state was obtained per 200 bp interval in the gene. We then annotated the genes by means of a consensus decision when multiple states were present for a single gene; i.e. the state of the gene was defined as the modus of all states present in the gene. Tissue expression of genes RNA sequencing data of 1,641 tissue samples with 45 unique tissue labels was derived from the GTEx consortium 39 . This set includes 313 brain samples over 13 unique brain regions (see Supplementary Table 18 for sample size per tissue). Of the 52 genes implicated by either the GWAS or the GWGWAS, 44 were included in the GTEx data. Normalization of the data was performed as described previously 45 . Briefly, genes with RPKM (Reads Per Kilobase Million) value smaller than 0.1 in at least 80% of the samples were removed. The remaining genes were log2 transformed (after using a pseudocount of 1), and finally a zero-mean normalization was applied. Proxy-replication in educational attainment For the replication analysis we used a subset of the data from ref. 21. In particular, we excluded the Erasmus Rucphen Family, the Minnesota Center for Twin and Family Research Study, the Swedish Twin Registry Study, the 23andMe data and all individuals from UK Biobank, to make sure there was no sample overlap with our IQ dataset. Genetic correlation between intelligence and EA in this non-overlapping subsample was rg=0.73, SE=0.03, P=1.4×10−163. The replication analysis was based on the phenotype EduYears, which measures the number of years of schooling completed. A total of 306 out of our 336 top SNPs (and 16 out of 18 independent lead SNPs) was available in the educational attainment sample. We performed a sign concordance analysis for the 16 independent lead SNPs, using the exact binomial test. For each independent signal we determined whether either the lead SNP had a P-value smaller than 0.05/16 in the educational attainment analysis, or another (correlated) top SNP in the same locus if this was not the case. All 47 genes implicated in the GWGAS for intelligence were available for look-up in the EA sample. For each gene we determined whether it had a P-value smaller than 0.05/47 in the EA analysis. Polygenic Risk Score analysis We used LDpred 16 to calculate the variance explained in intelligence in independent samples by a polygenic risk score based on our discovery analysis, as well as based on two previous GWAS studies for intelligence 5,6 . LDpred adjusts GWAS summary statistics for the effects of linkage disequilibrium (LD) by using an approximate Gibbs sampler that calculates posterior means of effects, conditional on LD information, when calculating polygenic risk scores. We used varying priors for the fraction of SNPs with non-zero effects (prior: 0.01, 0.05, 0.1, 0.5, 1, and an infinitesimal prior). Independent datasets available for PRS analyses are described in the Supplementary Note. Supplementary Material 1 2 3 4

0 comments Cited 166 times – based on 0 reviews      Review now

Bookmark

All references

Author and article information

Journal

Journal ID (nlm-journal-id): 9216904

Journal ID (pubmed-jr-id): 2419

Journal ID (nlm-ta): Nat Genet

Journal ID (iso-abbrev): Nat. Genet.

Title: Nature genetics

ISSN (Print): 1061-4036

ISSN (Electronic): 1546-1718

Publication date Nihms-submitted: 10 December 2019

Publication date (Electronic): 01 May 2019

Publication date (Print): May 2019

Publication date PMC-release: 13 January 2020

Volume: 51

Issue: 5

Pages: 793-803

Affiliations

[1 ]Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, US

[2 ]Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, US

[3 ]Medical and Population Genetics, Broad Institute, Cambridge, MA, US

[4 ]MRC Social, Genetic and Developmental Psychiatry Centre, King’s College London, London, GB

[5 ]NIHR BRC for Mental Health, King’s College London, London, GB

[6 ]Department of Biomedicine, University of Basel, Basel, CH

[7 ]Department of Psychiatry (UPK), University of Basel, Basel, CH

[8 ]Institute of Human Genetics, University of Bonn School of Medicine & University Hospital Bonn, Bonn, DE

[9 ]Centre for Human Genetics, University of Marburg, Marburg, DE

[10 ]Institute of Medical Genetics and Pathology, University Hospital Basel, Basel, CH

[11 ]Division of Psychiatry, University College London, London, GB

[12 ]Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA, US

[13 ]Department of Psychiatry and Psychotherapy, Charité - Universitätsmedizin, Berlin, DE

[14 ]Analytic and Translational Genetics Unit, Massachusetts General Hospital, Boston, MA, US

[15 ]iSEQ, Center for Integrative Sequencing, Aarhus University, Aarhus, DK

[16 ]Department of Biomedicine - Human Genetics, Aarhus University, Aarhus, DK

[17 ]Department of Clinical Neuroscience, Centre for Psychiatry Research, Karolinska Institutet, Stockholm, SE

[18 ]Department of Psychiatry, Psychosomatics and Psychotherapy, Center of Mental Health, University Hospital Würzburg, Würzburg, DE

[19 ]iPSYCH, The Lundbeck Foundation Initiative for Integrative Psychiatric Research, DK

[20 ]Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Copenhagen, DK

[21 ]Institute of Clinical Medicine, University of Oslo, Oslo, NO

[22 ]Department of Complex Trait Genetics, Center for Neurogenomics and Cognitive Research, Amsterdam Neuroscience, Vrije Universiteit Amsterdam, Amsterdam, NL

[23 ]deCODE Genetics / Amgen, Reykjavik, IS

[24 ]Queensland Brain Institute, The University of Queensland, Brisbane, QLD, AU

[25 ]Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, AU

[26 ]Division of Endocrinology and Center for Basic and Translational Obesity Research, Boston Children’s Hospital, Boston, MA, US

[27 ]Medical Research Council Centre for Neuropsychiatric Genetics and Genomics, Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, GB

[28 ]National Centre for Register-Based Research, Aarhus University, Aarhus, DK

[29 ]Centre for Integrated Register-based Research, Aarhus University, Aarhus, DK

[30 ]Molecular & Behavioral Neuroscience Institute, University of Michigan, Ann Arbor, MI, US

[31 ]NEUROSCIENCE, IRCCS - Istituto Di Ricerche Farmacologiche Mario Negri, Milano, IT

[32 ]Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, IL, US

[33 ]Psychiatry, Berkshire Healthcare NHS Foundation Trust, Bracknell, GB

[34 ]Psychiatry, Rush University Medical Center, Chicago, IL, US

[35 ]Center for Neonatal Screening, Department for Congenital Disorders, Statens Serum Institut, Copenhagen, DK

[36 ]Department of Psychiatry, Weill Cornell Medical College, New York, NY, US

[37 ]Department of Psychiatry and Psychotherapy, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, DE

[38 ]Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, SE

[39 ]Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, NO

[40 ]Psychiatry, UMC Utrecht Brain Center Rudolf Magnus, Utrecht, NL

[41 ]Human Genetics, University of California Los Angeles, Los Angeles, CA, US

[42 ]Institute of Psychiatric Phenomics and Genomics (IPPG), University Hospital, LMU Munich, Munich, DE

[43 ]Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, CA, US

[44 ]Molecular & Behavioral Neuroscience Institute and Department of Computational Medicine & Bioinformatics, University of Michigan, Ann Arbor, MI, US

[45 ]Psychiatry, University of California San Francisco, San Francisco, CA, US

[46 ]Instituto de Salud Carlos III, Biomedical Network Research Centre on Mental Health (CIBERSAM), Madrid, ES

[47 ]Department of Psychiatry, Hospital Universitari Vall d´Hebron, Barcelona, ES

[48 ]Department of Psychiatry and Forensic Medicine, Universitat Autònoma de Barcelona, Barcelona, ES

[49 ]Psychiatric Genetics Unit, Group of Psychiatry Mental Health and Addictions, Vall d´Hebron Research Institut (VHIR), Universitat Autònoma de Barcelona, Barcelona, ES

[50 ]Department of Psychiatry, Mood Disorders Program, McGill University Health Center, Montreal, QC, CA

[51 ]Division of Psychiatry, University of Edinburgh, Edinburgh, GB

[52 ]University of Iowa Hospitals and Clinics, Iowa City, IA, US

[53 ]Translational Genomics, USC, Phoenix, AZ, US

[54 ]Department of Translational Research in Psychiatry, Max Planck Institute of Psychiatry, Munich, DE

[55 ]Centre for Psychiatry, Queen Mary University of London, London, GB

[56 ]UCL Genetics Institute, University College London, London, GB

[57 ]Department of Psychiatry, Laboratory of Psychiatric Genetics, Poznan University of Medical Sciences, Poznan, PL

[58 ]Department of Neurosciences, University of California San Diego, La Jolla, CA, US

[59 ]Department of Radiology, University of California San Diego, La Jolla, CA, US

[60 ]Department of Psychiatry, University of California San Diego, La Jolla, CA, US

[61 ]Department of Cognitive Science, University of California San Diego, La Jolla, CA, US

[62 ]Applied Molecular Genomics Unit, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium

[63 ]Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, MD, US

[64 ]Department of Medical Genetics, Oslo University Hospital Ullevål, Oslo, NO

[65 ]NORMENT, KG Jebsen Centre for Psychosis Research, Department of Clinical Science, University of Bergen, Bergen, NO

[66 ]Department of Neurology, Oslo University Hospital, Oslo, NO

[67 ]NORMENT, KG Jebsen Centre for Psychosis Research, Oslo University Hospital, Oslo, NO

[68 ]Center for Statistical Genetics and Department of Biostatistics, University of Michigan, Ann Arbor, MI, US

[69 ]Department of Medical & Molecular Genetics, Indiana University, Indianapolis, IN, US

[70 ]Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Mannheim, DE

[71 ]Center for Neurobehavioral Genetics, University of California Los Angeles, Los Angeles, CA, US

[72 ]Department of Molecular Medicine and Surgery, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, SE

[73 ]Department of Clinical Neuroscience, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, SE

[74 ]Child and Adolescent Psychiatry Research Center, Stockholm, SE

[75 ]Department of Psychiatry and Psychotherapy, University Medical Center Göttingen, Göttingen, DE

[76 ]Department of Psychiatry, Dalhousie University, Halifax, NS, CA

[77 ]Department of Pathology and Laboratory Medicine, University of California Los Angeles, Los Angeles, CA, US

[78 ]Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, AU

[79 ]Department of Psychological Medicine, University of Worcester, Worcester, GB

[80 ]School of Biomedical Sciences, Plymouth University Peninsula Schools of Medicine and Dentistry, University of Plymouth, Plymouth, GB

[81 ]School of Psychiatry, University of New South Wales, Sydney, NSW, AU

[82 ]Neuroscience Research Australia, Sydney, NSW, AU

[83 ]Bioinformatics Research Centre, Aarhus University, Aarhus, DK

[84 ]Biostatistics, University of Minnesota System, Minneapolis, MN, US

[85 ]Mental Health Department, University Regional Hospital, Biomedicine Institute (IBIMA), Málaga, ES

[86 ]Department of Psychology, Eberhard Karls Universität Tübingen, Tubingen, DE

[87 ]Department of Psychiatry and Behavioral Sciences, Howard University Hospital, Washington, DC, US

[88 ]Center for Multimodal Imaging and Genetics, University of California San Diego, La Jolla, CA, US

[89 ]Psychiatrie Translationnelle, Inserm U955, Créteil, FR

[90 ]Faculté de Médecine, Université Paris Est, Créteil, FR

[91 ]Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, CA

[92 ]Neurogenetics Section, Centre for Addiction and Mental Health, Toronto, ON, CA

[93 ]Department of Psychiatry, University of Toronto, Toronto, ON, CA

[94 ]Institute of Medical Sciences, University of Toronto, Toronto, ON, CA

[95 ]Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital Frankfurt, Frankfurt am Main, DE

[96 ]Cell Biology, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, US

[97 ]Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, US

[98 ]ISGlobal, Barcelona, ES

[99 ]Psychiatry, Altrecht, Utrecht, NL

[100 ]Psychiatry, GGZ inGeest, Amsterdam, NL

[101 ]Psychiatry, VU medisch centrum, Amsterdam, NL

[102 ]Psychiatry, North East London NHS Foundation Trust, Ilford, GB

[103 ]Department of Neurodegenerative Diseases and Geropsychiatry, University Hospital Bonn, Bonn, DE

[104 ]Psychiatric and Neurodevelopmental Genetics Unit, Massachusetts General Hospital, Boston, MA, US

[105 ]HudsonAlpha Institute for Biotechnology, Huntsville, AL, US

[106 ]Department of Human Genetics, University of Michigan, Ann Arbor, MI, US

[107 ]Psychiatry, University of Illinois at Chicago College of Medicine, Chicago, IL, US

[108 ]Max Planck Institute of Psychiatry, Munich, DE

[109 ]Mental Health, NHS 24, Glasgow, GB

[110 ]Division of Psychiatry, Centre for Clinical Brain Sciences, University of Edinburgh, Edinburgh, GB

[111 ]Psychiatry, Brigham and Women’s Hospital, Boston, MA, US

[112 ]Department of Psychiatry and Psychotherapy, University of Bonn, Bonn, DE

[113 ]Department of Genetics, Harvard Medical School, Boston, MA, US

[114 ]Department of Psychiatry, University of Michigan, Ann Arbor, MI, US

[115 ]Genetic Cancer Susceptibility Group, International Agency for Research on Cancer, Lyon, FR

[116 ]Estonian Genome Center, University of Tartu, Tartu, EE

[117 ]Discipline of Biochemistry, Neuroimaging and Cognitive Genomics (NICOG) Centre, National University of Ireland, Galway, Galway, IE

[118 ]Neuropsychiatric Genetics Research Group, Dept of Psychiatry and Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, IE

[119 ]Institute of Neuroscience and Medicine (INM-1), Research Centre Jülich, Jülich, DE

[120 ]Research/Psychiatry, Veterans Affairs San Diego Healthcare System, San Diego, CA, US

[121 ]Department of Clinical Sciences, Psychiatry, Umeå University Medical Faculty, Umeå, SE

[122 ]Department of Clinical Psychiatry, Psychiatry Clinic, Clinical Center University of Sarajevo, Sarajevo, BA

[123 ]Department of Neurobiology, Care sciences, and Society, Karolinska Institutet and Center for Molecular Medicine, Karolinska University Hospital, Stockholm, SE

[124 ]Psychiatry, Harvard Medical School, Boston, MA, US

[125 ]Division of Clinical Research, Massachusetts General Hospital, Boston, MA, US

[126 ]Outpatient Clinic for Bipolar Disorder, Altrecht, Utrecht, NL

[127 ]Department of Psychiatry, Washington University in Saint Louis, Saint Louis, MO, US

[128 ]Department of Biochemistry and Molecular Biology II, Institute of Neurosciences, Center for Biomedical Research, University of Granada, Granada, ES

[129 ]Department of Neuroscience, Icahn School of Medicine at Mount Sinai, New York, NY, US

[130 ]Medicine, Psychiatry, Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, US

[131 ]Department of Health Sciences Research, Mayo Clinic, Rochester, MN, US

[132 ]Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, CA, US

[133 ]Rush University Medical Center, Chicago, IL, US

[134 ]Scripps Translational Science Institute, La Jolla, CA, US

[135 ]Faculty of Medicine, Department of Psychiatry, School of Health Sciences, University of Iceland, Reykjavik, IS

[136 ]Div Mental Health and Addiction, Oslo University Hospital, Oslo, NO

[137 ]NORMENT, University of Oslo, Oslo, NO

[138 ]Psychiatry and the Behavioral Sciences, University of Southern California, Los Angeles, CA, US

[139 ]Mood Disorders, PsyQ, Rotterdam, NL

[140 ]Institute for Medical Sciences, University of Aberdeen, Aberdeen, UK

[141 ]Research Division, Federal Institute for Drugs and Medical Devices (BfArM), Bonn, DE

[142 ]Centre for Addiction and Mental Health, Toronto, ON, CA

[143 ]Neurogenomics, TGen, Los Angeles, AZ, US

[144 ]Psychiatry, Psychiatrisches Zentrum Nordbaden, Wiesloch, DE

[145 ]Computational Sciences Center of Emphasis, Pfizer Global Research and Development, Cambridge, MA, US

[146 ]Department of Biostatistics, Princess Margaret Cancer Centre, Toronto, ON, CA

[147 ]Dalla Lana School of Public Health, University of Toronto, Toronto, ON, CA

[148 ]Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, GB

[149 ]Department of Mental Health, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, US

[150 ]Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, US

[151 ]A list of members appears in the Supplementary Note

[152 ]NORMENT, KG Jebsen Centre for Psychosis Research, Division of Mental Health and Addiction, Institute of Clinical Medicine and Diakonhjemmet Hospital, University of Oslo, Oslo, NO

[153 ]National Institute of Mental Health, Klecany, CZ

[154 ]Department of Psychiatry, University of Melbourne, Melbourne, Vic, AU

[155 ]Department of Psychiatry, University of Münster, Münster, DE

[156 ]Department of Psychiatry and Addiction Medicine, Assistance Publique - Hôpitaux de Paris, Paris, FR

[157 ]Paris Bipolar and TRD Expert Centres, FondaMental Foundation, Paris, FR

[158 ]UMR-S1144 Team 1: Biomarkers of relapse and therapeutic response in addiction and mood disorders, INSERM, Paris, FR

[159 ]Psychiatry, Université Paris Diderot, Paris, FR

[160 ]Psychiatry, University of Pennsylvania, Philadelphia, PA, US

[161 ]Division of Endocrinology, Children’s Hospital Boston, Boston, MA, US

[162 ]Centre for Affective Disorders, Institute of Psychiatry, Psychology and Neuroscience, London, GB

[163 ]Department of Psychiatry & Psychology, Mayo Clinic, Rochester, MN, US

[164 ]School of Medical Sciences, University of New South Wales, Sydney, NSW, AU

[165 ]Department of Human Genetics, University of Chicago, Chicago, IL, US

[166 ]Biometric Psychiatric Genetics Research Unit, Alexandru Obregia Clinical Psychiatric Hospital, Bucharest, RO

[167 ]Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, SE

[168 ]INSERM, Paris, FR

[169 ]Department of Medical & Molecular Genetics, King’s College London, London, GB

[170 ]Neuroscience Therapeutic Area, Janssen Research and Development, LLC, Titusville, NJ, US

[171 ]Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center and Institute of Oncology, Warsaw, PL

[172 ]School of Psychology, The University of Queensland, Brisbane, QLD, AU

[173 ]Research Institute, Lindner Center of HOPE, Mason, OH, US

[174 ]Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, GB

[175 ]Human Genetics Branch, Intramural Research Program, National Institute of Mental Health, Bethesda, MD, US

[176 ]Division of Mental Health and Addiction, Oslo University Hospital, Oslo, NO

[177 ]Division of Mental Health and Addiction, University of Oslo, Institute of Clinical Medicine, Oslo, NO

[178 ]Institute of Molecular and Cell Biology, University of Tartu, Tartu, EE

[179 ]Mental Health, Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology - NTNU, Trondheim, NO

[180 ]Psychiatry, St Olavs University Hospital, Trondheim, NO

[181 ]Psychosis Research Unit, Aarhus University Hospital, Risskov, DK

[182 ]Munich Cluster for Systems Neurology (SyNergy), Munich, DE

[183 ]University of Liverpool, Liverpool, GB

[184 ]Psychiatry and Human Genetics, University of Pittsburgh, Pittsburgh, PA, US

[185 ]Mental Health Services in the Capital Region of Denmark, Mental Health Center Copenhagen, University of Copenhagen, Copenhagen, DK

[186 ]Division of Psychiatry, Haukeland Universitetssjukehus, Bergen, NO

[187 ]Faculty of Medicine and Dentistry, University of Bergen, Bergen, NO

[188 ]Human Genetics and Computational Biomedicine, Pfizer Global Research and Development, Groton, CT, US

[189 ]College of Medicine Institute for Genomic Health, SUNY Downstate Medical Center College of Medicine, Brooklyn, NY, US

[190 ]Department of Clinical Genetics, Amsterdam Neuroscience, Vrije Universiteit Medical Center, Amsterdam, NL

[191 ]Department of Neurology and Neurosurgery, McGill University, Faculty of Medicine, Montreal, QC, CA

[192 ]Montreal Neurological Institute and Hospital, Montreal, QC, CA

[193 ]Department of Biomedical and NeuroMotor Sciences, University of Bologna, Bologna, IT

[194 ]Department of Psychiatry, Massachusetts General Hospital, Boston, MA, US

[195 ]Psychiatric and Neurodevelopmental Genetics Unit (PNGU), Massachusetts General Hospital, Boston, MA, US

[196 ]Faculty of Medicine, University of Iceland, Reykjavik, IS

[197 ]Department of Psychiatry, Hospital Namsos, Namsos, NO

[198 ]Department of Mental Health, Norwegian University of Science and Technology, Trondheim NO

[199 ]Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, US

[200 ]Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, NC, US

[201 ]Department of Psychiatry, McGill University, Montreal, QC, CA

[202 ]Dept of Psychiatry, Sankt Olavs Hospital Universitetssykehuset i Trondheim, Trondheim, NO

[203 ]Clinical Institute of Neuroscience, Hospital Clinic, University of Barcelona, IDIBAPS, CIBERSAM, Barcelona, ES

[204 ]Institute of Biological Psychiatry, MHC Sct. Hans, Mental Health Services Copenhagen, Roskilde, DK

[205 ]Department of Clinical Medicine, University of Copenhagen, Copenhagen, DK

[206 ]Psychiatry, Indiana University School of Medicine, Indianapolis, IN, US

[207 ]Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN, US

Author notes

[†]

Equal contribution

[*]

Co-last authors

Author Contributions:

Writing group: E.A.S., G.B., A.J.F., A.McQuillin, S.R., J.R.I.C., N.M., N.R.W., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A., J.K.

PGC BD PI group: E.A.S., G.B., A.J.F., A.McQuillin, D.Curtis, R.H.P., R.A., I.A., M.A., L.B., B.T.B., F.B., W.H.B., J.M.B., D.H.R.B., M.Boehnke, A.D.B., A.C., N.C., U.D., T.Esko, B.E., M.Frye, J.M.F., E.S.G., M.G., F.G., M.G-S., J.H., D.M.H., C.M.H., I.J., L.A.J., R.S.K., M.Landén, M.Leboyer, C.M.L., Q.S.L., J.Lissowska, N.G.M., S.L.M., A.M.M., F.J.M., I.M., A.Metspalu, P.B.Mitchell, G.M., O.M., P.B.Mortensen, B.M-M., R.M.M., B.M.N., V.N., M.N., M.M.N., M.C.O’D., K.J.O., M.J.O., S.A.P., C.P., M.T.P., J.A.R-Q., M.Ribasés, M.Rietschel, G.A.R., M.Schalling, P.R.S., T.G.S., A.S., J.W.S., H.S., K.S., E.Stordal, G.T., A.E.V., E.V., J.B.V., T.W., J.I.N., A.D.F., H.J.E., S.C., R.A.O., L.J.S., O.A.A., J.K., P.S.

Bioinformatics: E.A.S., G.B., A.J.F., J.R.I.C., H.A.G., P.A.H., S.E.B., D.W.C., V.E-P., C.G., M.L.H., S.H., R.Karlsson, M.Leber, C.Liu, F.Meng, L.M.O.L., A.P.S.O., C.S.R., P.R., P.D.S., M.Steffens, S.Szelinger, T.E.T., S.X., P.Zandi, eQTLGen Consortium, BIOS Consortium, T.Esko, E.S.G., Q.S.L., G.A.R., H.S.

Clinical: A.McQuillin, M.M., E.A., N.A-R., A.A., N.B., M.Bauer, C.B.P., E.B., M.P.B., M.Budde, M.Burmeister, W.Byerley, M.C., P.C., W.C., D.Curtis, P.M.C., J.R.D., T.Elvsåshagen, L.Forty, C.F., K.G., J.Garnham, M.G.P., K.G-S., M.J.G., J.Grove, J.G-P., M.Hautzinger, U.H., M.Hipolito, A.J., J.L.K., S.K-S., M.K., R.Kupka, C.Lavebratt, J.Lawrence, W.B.L., S.L., D.J.M., P.B.Mahon, W.M., L.Martinsson, P.M., M.G.M., H.M., A.N.A., E.A.N., C.O’D., L.O., U.Ö., R.H.P., A.Perry, A.Pfennig, J.B.P., E.J.R., A.R., J.P.R., F.R., M.Rivera, W.A.S., C.S.W., E.Sigurdsson, C.S., O.B.S., J.L.S., A.T.S., D.S.C., J.S.S., F.S., J.S., R.C.T., H.V., T.W.W., A.H.Y., R.A., I.A., M.A., B.T.B., F.B., D.H.R.B., A.D.B., A.C., N.C., U.D., B.E., M.Frye, E.S.G., M.G., F.G., M.G-S., J.H., I.J., L.A.J., R.S.K., G.K., M.Landén, J.Lissowska, N.G.M., F.Mayoral, S.L.M., A.M.M., F.J.M., I.M., P.B.Mitchell, G.M., O.M., P.B.Mortensen, V.N., M.C.O’D., K.J.O., M.J.O., C.P., M.T.P., J.A.R-Q., M.Rietschel, T.G.S., A.S., J.W.S., E.Stordal, A.E.V., E.V., J.I.N., A.D.F.

Genomic assays/data generation: G.B., A.J.F., E.A., D.A., M.B-H., C.B.P., J.B-G., T-K.C., D.W.C., C.Cruceanu, F.D., J.D-F., S.D., S.B.F., J.F., M.G.P., E.K.G., P.H., S.J., R.Kandaswamy, A.C.K., S.E.L., A.Maaser, J.D.M., L.Milani, G.W.M., D.W.M., T.W.M., E.R., C.S-M., T.S., C.S.H., S.Szelinger, J.T., S.H.W., P.Zhang, A.C., T.Esko, J.M.F., E.S.G., M.G., D.M.H., R.M.M., M.M.N., M.Ribasés, G.A.R., G.T., S.C.

Obtained funding for BD samples: G.B., H.A., N.A-R., J.D.B., W.Bunney, J.R.D., N.B.F., L.Frisén, M.J.G., S.J., J.A.K., C.Lavebratt, S.L., P.M., G.W.M., U.Ö., J.B.P., M.Rivera, A.F.S., C.S.W., S.J.W., T.W.W., A.H.Y., M.A., B.T.B., W.H.B., J.M.B., M.Boehnke, A.D.B., A.C., N.C., M.Frye, J.M.F., E.S.G., M.G., M.G-S., I.J., L.A.J., M.Landén, M.Leboyer, C.M.L., N.G.M., A.Metspalu, P.B.Mitchell, O.M., P.B.Mortensen, B.M.N., M.N., M.M.N., M.C.O’D., M.J.O., C.P., M.T.P., M.Rietschel, G.A.R., P.R.S., T.G.S., J.W.S., G.T., J.B.V., T.W., J.I.N., H.J.E., R.A.O., P.S.

Statistical analysis: E.A.S., G.B., S.R., V.T., M.M., Y.W., J.R.I.C., H.A.G., C.A.d.L., S.Steinberg, J.M.W.P., M.T., E.M.B., T.H.P., P.A.H., A.L.R., L.A., N.A-R., T.D.A., V.A., S.A., J.A.B., R.B., S.E.B., J.B., F.C., K.C., A.W.C., D.Chen, C.Churchhouse, A.M.D., S.d.J., A.L.D., A.D., V.E-P., C.C.F., M.Flickinger, T.M.F., D.G., C.G., J.Goldstein, S.D.G., T.A.G., J.Grove, W.G., M.L.H., D.H., L.H., J.S.J., R.Karlsson, M.Leber, P.H.L., J.Z.L., S.M., S.E.M., D.W.M., N.M., H.N., C.M.N., L.M.O.L., A.P.S.O., S.M.P., C.S.R., P.R., D.M.R., N.J.S., O.B.S., T.E.T., W.W., W.X., P.Zandi, P.Zhang, S.Z., eQTLGen Consortium, BIOS Consortium, J.M.B., A.D.B., M.J.D., E.S.G., F.G., Q.S.L., B.M-M., D.P., H.S., P.F.S., N.R.W., P.S.

[& ]Correspondence to: jkelsoe@ 123456ucsd.edu or eli.stahl@ 123456mssm.edu

Article

Manuscript ID: NIHMS1524328

DOI: 10.1038/s41588-019-0397-8

PMC ID: 6956732

PubMed ID: 31043756

SO-VID: 88f325ac-08f0-4d46-b3e0-379b8be12cc3

License:

Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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

Read this article at

Abstract

Related collections

UCL: UN SDG 03 Good Health and Well-Being

Most cited references 29

GWAS of 126,559 individuals identifies genetic variants associated with educational attainment.

The prevalence and burden of bipolar disorder: findings from the Global Burden of Disease Study 2013.

Genome-wide association meta-analysis of 78,308 individuals identifies new loci and genes influencing human intelligence

Author and article information

Journal

Affiliations

Author notes

Article

History

Categories

Comments

Comment on this article

Similar content 305

Cited by 557