Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder

Marleen H. M. de Moor(Vrije Universiteit Amsterdam), Stéphanie M. van den Berg(University of Twente), Karin J. H. Verweij(QIMR Berghofer Medical Research Institute), Robert F. Krueger(University of Minnesota), Michelle Luciano(University of Edinburgh), Alejandro Arias Vásquez(Radboud University Nijmegen), Lindsay Matteson(University of Minnesota), Jaime Derringer(University of Illinois Urbana-Champaign), Tõnu Esko(University of Tartu), Najaf Amin(Erasmus MC), Scott D. Gordon(QIMR Berghofer Medical Research Institute), Narelle K. Hansell(QIMR Berghofer Medical Research Institute), Amy Hart(University of Chicago), Ilkka Seppälä(Tampere University), Jennifer E. Huffman(Western General Hospital), Bettina Konte, Jari Lahti(University of Helsinki), Minyoung Lee(Virginia Commonwealth University), Mike Miller(University of Minnesota), Teresa Nutile(Institute of Genetics and Biophysics), Toshiko Tanaka(National Institutes of Health), Alexander Teumer(Universitätsmedizin Greifswald), Alexander Viktorin(Karolinska Institutet), Juho Wedenoja(University of Helsinki), Gonçalo R. Abecasis(University of Michigan), Daniel E. Adkins(Virginia Commonwealth University), Arpana Agrawal(Washington University in St. Louis), Jüri Allïk(Estonian Academy of Sciences), Katja Appel(Universitätsmedizin Greifswald), T. Bernard Bigdeli(Virginia Commonwealth University), Fabio Busonero(Institute of Genetic and Biomedical Research), Harry Campbell(University of Edinburgh), Paul T. Costa(Duke University), George Davey Smith(University of Bristol), Gail Davies(University of Edinburgh), Harriet de Wit(University of Chicago), Jun Ding(National Institutes of Health), Barbara E. Engelhardt(Princeton University), Johan G. Eriksson(University of Helsinki), Iryna O. Fedko(Vrije Universiteit Amsterdam), Luigi Ferrucci(National Institutes of Health), Barbara Franke(Radboud University Nijmegen), Ina Giegling, Richard A. Grucza(Washington University in St. Louis), Annette M. Hartmann, Andrew C. Heath(Washington University in St. Louis), Kati Heinonen(University of Helsinki), Anjali K. Henders(QIMR Berghofer Medical Research Institute), Georg Homuth(Universität Greifswald), Jouke‐Jan Hottenga(Vrije Universiteit Amsterdam), William G. Iacono(University of Minnesota), Joost Janzing(Radboud University Nijmegen), Markus Jokela(University of Helsinki), Robert Karlsson(Karolinska Institutet), John P. Kemp(Translational Research Institute), Matthew G. Kirkpatrick(University of Chicago), Antti Latvala(University of Helsinki), Terho Lehtimäki(Tampere University), David C. Liewald(University of Edinburgh), Pamela A. F. Madden(Washington University in St. Louis), Chiara Magri(University of Brescia), Patrik K. E. Magnusson(Karolinska Institutet), Jonathan Marten(Western General Hospital), Andrea Maschio(Institute of Genetic and Biomedical Research), Sarah E. Medland(QIMR Berghofer Medical Research Institute), Evelin Mihailov(University of Tartu), Yuri Milaneschi(Amsterdam Neuroscience), Grant W. Montgomery(QIMR Berghofer Medical Research Institute), Matthias Nauck(Universitätsmedizin Greifswald), Klaasjan G. Ouwens(Vrije Universiteit Amsterdam), Aarno Palotie(University of Helsinki), Erik Pettersson(Karolinska Institutet), Ozren Polašek(University of Split), Yong Qian(National Institutes of Health), Laura Pulkki-Råbäck(University of Helsinki), Olli T. Raitakari(University of Turku), Anu Realo(University of Tartu), Richard J. Rose(Indiana University Bloomington), Daniela Ruggiero(Institute of Genetics and Biophysics), Carsten Oliver Schmidt(Universitätsmedizin Greifswald), Wendy S. Slutske(University of Missouri), Rossella Sorice(Institute of Genetics and Biophysics), John M. Starr(Alzheimer Scotland), Beaté St Pourcain(University Of Bristol Dental Hospital), Angelina R. Sutin(Florida State University), Nicholas J. Timpson(University of Bristol), Holly Trochet(Western General Hospital), Sita H. Vermeulen(Radboud University Nijmegen), Eero Vuoksimaa(University of Helsinki), Elisabeth Widén(University of Helsinki), Jasper Wouda(Vrije Universiteit Amsterdam), Margaret J. Wright(QIMR Berghofer Medical Research Institute), Lina Zgaga(Trinity College Dublin), David J. Porteous(Western General Hospital), Alessandra Minelli(University of Brescia), Abraham A. Palmer(University of Chicago), Dan Rujescu, Marina Ciullo(Institute of Genetics and Biophysics), Caroline Hayward(Western General Hospital), Igor Rudan(University of Edinburgh), Andres Metspalu(Estonian Academy of Sciences), Jaakko Kaprio(University of Helsinki), Ian J. Deary(University of Edinburgh), Katri Räikkönen(University of Helsinki), James F. Wilson(University of Edinburgh), Liisa Keltikangas–Järvinen(University of Helsinki), Laura J. Bierut(Washington University in St. Louis), John M. Hettema(Virginia Commonwealth University), Hans J. Grabe(Universitätsmedizin Greifswald), Cornelia M. van Duijn(Erasmus MC), David M. Evans(Translational Research Institute), David Schlessinger(National Institutes of Health), Nancy L. Pedersen(Institute of Genetics and Biophysics), Antonio Terracciano(Florida State University), Matt McGue(University of Minnesota), Brenda W.J.H. Penninx(Amsterdam Neuroscience), Nicholas G. Martin(QIMR Berghofer Medical Research Institute), Dorret I. Boomsma(Vrije Universiteit Amsterdam)
JAMA Psychiatry
May 20, 2015
10.1001/jamapsychiatry.2015.0554
Cited by 363Open Access
Full Text

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.

Related Papers

No related papers found

Powered by citation graph analysis