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JAMA Psychiatry. 2015 Jul;72(7):642-50. doi: 10.1001/jamapsychiatry.2015.0554.

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

Genetics of Personality Consortium, de Moor MH1, van den Berg SM2, Verweij KJ3, Krueger RF4, Luciano M5, Arias Vasquez A6, Matteson LK4, Derringer J7, Esko T8, Amin N9, Gordon SD10, Hansell NK10, Hart AB11, Seppälä I12, Huffman JE13, Konte B14, Lahti J15, Lee M16, Miller M4, Nutile T17, Tanaka T18, Teumer A19, Viktorin A20, Wedenoja J21, Abecasis GR22, Adkins DE23, Agrawal A24, Allik J25, Appel K26, Bigdeli TB16, Busonero F27, Campbell H28, Costa PT29, Davey Smith G30, Davies G5, de Wit H31, Ding J18, Engelhardt BE32, Eriksson JG33, Fedko IO34, Ferrucci L18, Franke B35, Giegling I14, Grucza R24, Hartmann AM14, Heath AC24, Heinonen K36, Henders AK10, Homuth G37, Hottenga JJ34, Iacono WG4, Janzing J38, Jokela M36, Karlsson R20, Kemp JP39, Kirkpatrick MG31, Latvala A40, Lehtimäki T12, Liewald DC5, Madden PA24, Magri C41, Magnusson PK20, Marten J13, Maschio A27, Medland SE10, Mihailov E42, Milaneschi Y43, Montgomery GW10, Nauck M44, Ouwens KG34, Palotie A45, Pettersson E20, Polasek O46, Qian Y18, Pulkki-Råback L36, Raitakari OT47, Realo A48, Rose RJ49, Ruggiero D17, Schmidt CO19, Slutske WS50, Sorice R17, Starr JM51, St Pourcain B52, Sutin AR53, Timpson NJ30, Trochet H13, Vermeulen S54, Vuoksimaa E21, Widen E55, Wouda J56, Wright MJ10, Zgaga L57, Porteous D58, Minelli A41, Palmer AA59, Rujescu D14, Ciullo M17, Hayward C60, Rudan I28, Metspalu A61, Kaprio J62, Deary IJ5, Räikkönen K36, Wilson JF28, Keltikangas-Järvinen L36, Bierut LJ24, Hettema JM16, Grabe HJ63, van Duijn CM9, Evans DM39, Schlessinger D18, Pedersen NL17, Terracciano A64, McGue M65, Penninx BW43, Martin NG10, Boomsma DI34.

Author information

1
Department of Clinical Child and Family Studies, VU University Amsterdam, Amsterdam, the Netherlands2Department of Methods, VU University Amsterdam, Amsterdam, the Netherlands3Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Ne.
2
Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands.
3
Department of Developmental Psychology, EMGO Institute for Health and Care Research, VU University Amsterdam, Amsterdam, the Netherlands6QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia.
4
Department of Psychology, University of Minnesota, Minneapolis.
5
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland9Department of Psychology, University of Edinburgh, Edinburgh, Scotland.
6
Department of Cognitive Neuroscience, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands11Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, the Netherlands12Department of Psychiatry, Radboud University.
7
Department of Psychology, University of Illinois at Urbana-Champaign, Champaign.
8
Estonian Genome Center, University of Tartu, Tartu, Estonia.
9
Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
10
QIMR Berghofer Medical Research Institute, Herston, Brisbane, Australia.
11
Department of Human Genetics, University of Chicago, Chicago, Illinois.
12
Department of Clinical Chemistry, Fimlab Laboratories and School of Medicine, University of Tampere, Tampere, Finland.
13
Medical Research Council Human Genetics, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland.
14
Department of Psychiatry, University of Halle, Halle, Germany.
15
Folkhälsan Research Center, Helsinki, Finland22Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
16
Department of Psychiatry, Virginia Institute for Psychiatric and Behavioral Genetics, Virginia Commonwealth University, Richmond.
17
Institute of Genetics and Biophysics "A. Buzzati-Traverso," National Research Council of Italy, Naples, Italy.
18
National Institute on Aging, National Institutes of Health, Baltimore, Maryland.
19
Institute for Community Medicine, University Medicine Greifswald, Greifswald, Germany.
20
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
21
Department of Public Health, University of Helsinki, Helsinki, Finland.
22
Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor.
23
Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond.
24
Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri.
25
Department of Psychology, University of Tartu, Tartu, Estonia33Estonian Academy of Sciences, Tallinn, Estonia.
26
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany.
27
Istituto di Ricerca Genetica e Biomedica, National Research Council of Italy, Monserrato, Italy.
28
Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland.
29
Behavioral Medicine Research Center, Duke University School of Medicine, Durham, North Carolina.
30
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England.
31
Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois.
32
Department of Computer Science, Princeton University, Princeton, New Jersey.
33
Folkhälsan Research Center, Helsinki, Finland41Department of General Practice and Primary Health Care, University of Helsinki and Helsinki University Hospital, Helsinki, Finland42Vasa Central Hospital, Vasa, Finland43National Institute for Health and Welf.
34
Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands.
35
Donders Institute for Cognitive Neuroscience, Radboud University Nijmegen, Nijmegen, the Netherlands12Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands13Department of Human Genetics, Radboud University Nijmege.
36
Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland.
37
Interfaculty Institute for Genetics and Functional Genomics, University of Greifswald, Greifswald, Germany.
38
Department of Psychiatry, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands.
39
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England45University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
40
Department of Public Health, University of Helsinki, Helsinki, Finland43National Institute for Health and Welfare, Helsinki, Finland.
41
Department of Molecular and Translational Medicine, University of Brescia, Brescia, Italy.
42
Estonian Genome Center, University of Tartu, Tartu, Estonia47Department of Biotechnology, University of Tartu, Tartu, Estonia.
43
Department of Psychiatry, EMGO+ Institute, Neuroscience Campus Amsterdam, VU University Medical Center, Amsterdam, the Netherlands.
44
Institute of Clinical Chemistry and Laboratory Medicine, University Medicine Greifswald, Greifswald, Germany.
45
Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, England51Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
46
Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia.
47
Department of Clinical Physiology and Nuclear Medicine, Turku University Hospital, Turku, Finland54Research Centre of Applied and Preventive Cardiovascular Medicine, University of Turku, Turku, Finland.
48
Department of Psychology, University of Tartu, Tartu, Estonia.
49
Department of Psychological and Brain Sciences, Indiana University, Bloomington.
50
Department of Psychological Sciences and Missouri Alcoholism Research Center, University of Missouri, Columbia.
51
Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland57Alzheimer Scotland Dementia Research Centre, University of Edinburgh, Edinburgh, Scotland.
52
Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England58School of Oral and Dental Sciences, University of Bristol, Bristol, England59School of Experimental Psychology, Unive.
53
National Institute on Aging, National Institutes of Health, Baltimore, Maryland60College of Medicine, Florida State University, Tallahassee.
54
Department of Human Genetics, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands61Department for Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands.
55
Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
56
Department of Biological Psychology, VU University Amsterdam, Amsterdam, the Netherlands4Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands.
57
Institute for Population Health Sciences and Informatics, University of Edinburgh, Edinburgh, Scotland62Department of Public Health and Primary Care, Trinity College Dublin, Dublin, Ireland.
58
Medical Genetics Section, University of Edinburgh, Centre for Genomic and Experimental Medicine, Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh, Scotland.
59
Department of Human Genetics, University of Chicago, Chicago, Illinois39Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois.
60
Medical Research Council Human Genetics, MRC Institute of Genetics and Molecular Medicine, University of Edinburgh, Western General Hospital, Edinburgh, Scotland64Generation Scotland, University of Edinburgh, Centre for Genomic and Experimental Medicine.
61
Estonian Genome Center, University of Tartu, Tartu, Estonia33Estonian Academy of Sciences, Tallinn, Estonia.
62
Department of Public Health, University of Helsinki, Helsinki, Finland43National Institute for Health and Welfare, Helsinki, Finland51Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland.
63
Department of Psychiatry and Psychotherapy, University Medicine Greifswald, Greifswald, Germany65Department of Psychiatry and Psychotherapy, HELIOS Hospital Stralsund, Stralsund, Germany.
64
Folkhälsan Research Center, Helsinki, Finland60College of Medicine, Florida State University, Tallahassee.
65
Department of Psychology, University of Minnesota, Minneapolis66Institute of Public Health, University of Southern Denmark, Odense, Denmark.

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.

PMID:
25993607
PMCID:
PMC4667957
DOI:
10.1001/jamapsychiatry.2015.0554
[Indexed for MEDLINE]
Free PMC Article

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