Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder
Year: 2015
Type: review
Abstract: IMPORTANCE: Neuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases). OBJECTIVES: To identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD. DESIGN, SETTING, AND PARTICIPANTS: Genome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014. MAIN OUTCOMES AND MEASURES: Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts. RESULTS: A genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12 < P < .05) and MDD (4.02 × 10-9 < P < .05) in the 2 other cohorts. CONCLUSIONS AND RELEVANCE: This study identifies a novel locus for neuroticism. The variant is located in a known gene that has been associated with bipolar disorder and schizophrenia in previous studies. In addition, the study shows that neuroticism is influenced by many genetic variants of small effect that are either common or tagged by common variants. These genetic variants also influence MDD. Future studies should confirm the role of the MAGI1 locus for neuroticism and further investigate the association of MAGI1 and the polygenic association to a range of other psychiatric disorders that are phenotypically correlated with neuroticism.
Source: JAMA Psychiatry
Authors: Marleen H. M. de Moor, Stéphanie M. van den Berg, Karin J. H. Verweij, Robert F. Krueger, Michelle Luciano, Alejandro Arias Vasquez, Lindsay K. Matteson, Jaime Derringer, Tõnu Esko, Najaf Amin, Scott D. Gordon, Narelle K. Hansell, Amy B. Hart, Ilkka Seppälä, Jennifer E. Huffman, Bettina Konte, Jari Lahti, Minyoung Lee, Mike Miller, Teresa Nutile, Toshiko Tanaka, Alexander Teumer, Alexander Viktorin, Juho Wedenoja, Goncalo R. Abecasis, Daniel E. Adkins, Arpana Agrawal, Jüri Allik, Katja Appel, Timothy B. Bigdeli, Fabio Busonero, Harry Campbell, Paul T. Costa, George Davey Smith, Gail Davies, Harriet de Wit, Jun Ding, Barbara E. Engelhardt, Johan G. Eriksson, Iryna O. Fedko, Luigi Ferrucci, Barbara Franke, Ina Giegling, Richard Grucza, Annette M. Hartmann, Andrew C. Heath, Kati Heinonen, Anjali K. Henders, Georg Homuth, Jouke-Jan Hottenga, William G. Iacono, Joost Janzing, Markus Jokela, Robert Karlsson, John P. Kemp, Matthew G. Kirkpatrick, Antti Latvala, Terho Lehtimäki, David C. Liewald, Pamela A. F. Madden, Chiara Magri, Patrik K. E. Magnusson, Jonathan Marten, Andrea Maschio, Sarah E. Medland, Evelin Mihailov, Yuri Milaneschi, Grant W. Montgomery, Matthias Nauck, Klaasjan G. Ouwens, Aarno Palotie, Erik Pettersson, Ozren Polasek, Yong Qian, Laura Pulkki-Råback, Olli T. Raitakari, Anu Realo, Richard J. Rose, Daniela Ruggiero, Carsten O. Schmidt, Wendy S. Slutske, Rossella Sorice, John M. Starr, Beate St Pourcain, Angelina R. Sutin, Nicholas J. Timpson, Holly Trochet, Sita Vermeulen, Eero Vuoksimaa, Elisabeth Widen, Jasper Wouda, Margaret J. Wright, Lina Zgaga, David Porteous, Alessandra Minelli, Abraham A. Palmer, Dan Rujescu, Marina Ciullo, Caroline Hayward, Igor Rudan, Andres Metspalu, Jaakko Kaprio, Ian J. Deary, Katri Räikkönen, James F. Wilson, Liisa Keltikangas-Järvinen, Laura J. Bierut, John M. Hettema, Hans J. Grabe, Cornelia M. van Duijn, David M. Evans, David Schlessinger, Nancy L. Pedersen, Antonio Terracciano, Matt McGue, Brenda W. J. H. Penninx, Nicholas G. Martin, Dorret I. Boomsma
Institutions: Vrije Universiteit Amsterdam, University of Twente, QIMR Berghofer Medical Research Institute, Amsterdam Public Health, University of Minnesota, University of Edinburgh, Radboud University Nijmegen, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, University of Illinois Urbana-Champaign, University of Tartu, Erasmus MC, University of Chicago, Fimlab (Finland), University of Tampere, Western General Hospital, Institute of Genetics and Cancer, Medical Research Council, Martin Luther University Halle-Wittenberg, University of Helsinki, Folkhälsans Forskningscentrum, Virginia Commonwealth University, Institute of Genetics and Biophysics, National Research Council, National Institutes of Health, National Institute on Aging, Universitätsmedizin Greifswald, Karolinska Institutet, University of Michigan, Washington University in St. Louis, Estonian Academy of Sciences, Institute of Genetic and Biomedical Research, Duke University, Duke Medical Center, University of Bristol, MRC Integrative Epidemiology Unit, Princeton University, Helsinki University Hospital, Finnish Institute for Health and Welfare, Vaasa Central Hospital, Universität Greifswald, Translational Research Institute, The University of Queensland, University of Brescia, Amsterdam Neuroscience, Amsterdam UMC Location Vrije Universiteit Amsterdam, Wellcome Sanger Institute, Institute for Molecular Medicine Finland, University of Split, University of Turku, Turku University Hospital, Indiana University Bloomington, Indiana University, University of Missouri, Alzheimer Scotland, Florida State University, Trinity College Dublin, University of Southern Denmark
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Funders: Florida State University, Princeton University, University of Missouri, University of Minnesota, Helsingin Yliopisto, Eesti Teaduste Akadeemia, Virginia Commonwealth University, Wellcome Trust, School of Public Health, University of Michigan, QIMR Berghofer Medical Research Institute, University of Bristol, Trinity College Dublin, ZonMw, Radboud Universiteit, Vrije Universiteit Amsterdam, Nederlandse Organisatie voor Wetenschappelijk Onderzoek, Karolinska Institutet, Tampereen Yliopisto, Samfundet Folkhälsan, Turun Yliopisto, Radboud Universitair Medisch Centrum, Università degli Studi di Brescia, Tartu Ülikool, Turun Yliopistollinen Keskussairaala, Terveyden ja hyvinvoinnin laitos, Centre for Cognitive Ageing and Cognitive Epidemiology, Universität Greifswald, National Institutes of Health, University of Illinois at Urbana-Champaign, School of Medicine, Duke University, Medical Research Council, Biotechnology and Biological Sciences Research Council, Erasmus Universitair Medisch Centrum Rotterdam, Diamantina Institute, University of Queensland, National Institute on Alcohol Abuse and Alcoholism, National Institute of Mental Health, National Institute on Drug Abuse, National Human Genome Research Institute, National Cancer Institute, Institute of Genetics
Awards: G1104670545, The Genetics of Vulnerability to Nicotine Addictions, Centre for Cognitive Ageing & Cognitive Epidemiology, Twin Study of Female Alcoholism and Other Disorders, Genes, Environments & Interventions: Understanding and Addressing Alcohol Misuse, Substance Abuse & Behavioral Disinhibition: Integrating Genes & Environment, G16286648, G178382592, ALSPAC: consolidation of a two generation cell line backed resource, for the study of the environment and genetic determinants of health and development from before birth to late puberty., Genetic Epideniologic Models of Alcohol Abuse, G2238725043, USE &ABUSE OF ALCOHOL--A BEHAVIOR-GENETICS PERSPECTIVE, DIAGNOSTIC CENTER FOR LINKAGE STUDIES OF SCHIZOPHRENIA, Study of Addiction: Genetics and Environment, Molecular Epidemiology of Alcoholism 3 - EDAC Families, Statistical models to investigate long-distance QTL transcription regulation, Molecular Genetics of Schizophrenia, MARC: Genetic Epidemiology of Alcoholism & Comorbidity, LINKAGE STUDIES OF SCHIZOPHRENIA, Molecular Genetics of Schizophrenia, Adolescent Alcohol Abuse: A Twin-Study Perspective, Novel Methods to Map Stimulant QTLs in Advanced Intercross Lines, Molecular Genetics of Schizophrenia, Molecular Genetics of Schizophrenia, GENETIC AND EPIDEMIOLOGICAL MODELS OF ALCOHOL ABUSE, The Collaborative Genetic Study of Nicotine Dependence, The Avon Longitudinal Study for Parents and Children: An international resource for population genomic and lifecourse epidemiology. Core programme support 2014-2019., Genome Wide Association Coordinating Center, The Avon Longitudinal Study of Parents and Children: An international resource for population
genomics and lifecourse epidemiology. Core Programme Support 2011-2015 and Core programme support 2014-2019, Molecular Genetics of Schizophrenia, DIAGNOSTIC CENTER FOR SCHIZOPHRENIA LINKAGE STUDIES, A Genome-Wide Association Study of Schizophrenia, Twin Study of ADHD, CD and Substance Abuse, G5652732059, Molecular Genetics of Schizophrenia, Biomedical Training in Alcoholism Research, BEHAVIORAL PRECURSORS OF ALCOHOLISM--TWIN FAMILY STUDIES, JH/CIDR Genotyping for Genome-Wide Association Studies, Stratifying Resilience and Depression Longitudinally (STRADL), Molecular Genetics of Schizophrenia, G6759593836, A Longitudinal Study of Adopted Youth and Their Families, Refining Phenotypic Measures of Nicotine Withdrawal, Molecular Genetics of Schizophrenia, G70080636, A genome-wide association study of non-pathological cognitive ageing, Molecular Epidemiology of Alcoholism 2- Big Sibships, G7083800363, Molecular Genetics of Schizophrenia, Systems Genetic Analysis of Methamphetamine's Motivational Effects in a Mouse AIL, Genome-wide Association Study of Schizophrenia, Substance Abuse & Behavioral Disinhibition: Integrating Genes & Environment, Adolescent Alcohol Abuse: A Twin-Study Perspective, Genetic Epidemiology of Pathological Gambling, Adult consequences of youth substance use: Twin study enriched for SUD risk, The development of alcohol misuse and related problems from adolescence to early midlife, Twin Family Study of Vulnerability to Substance Abuse, Integration of Genomics & Transcriptomics in Normal Twins & Major Depression, G8263226176, G8267674335, Sibling Models of Adolescent Alcohol Use and Abuse, Determinants of Drug Preference in Humans, Statistical models to investigate long-distance QTL transcription regulation, Major Depression: Stage 1 Genomewide Association in Population-Based Samples, Molecular Genetics of Schizophrenia, THE GENETICS OF VULNERABILITY TO NICOTINE ADDICTIONS, Neuropsychopharmacology Training for Drug Abuse Research, Research Training - Mental Health Behavior Genetics, Collaborative Study on the Genetics of Alcoholism (COGA).
OpenAlex ID: W1914301979