Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder
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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.
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The UP is a cognitive-behavioral intervention designed to address neuroticism, which has been considered a predictor of depressive and anxiety disorders.
“The Unified Protocol for Transdiagnostic Treatment of Emotional Disorders (UP)26 is a cognitive-behavioral intervention designed to address neuroticism, which has been considered a predictor of depressive and anxiety disorders.27-30”
From Improved quality of life and reduced depressive symptoms in medical students after a single-session intervention (2020) · cites this paper as [27]
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- Authors
- de Moor, M. H. M., van den Berg, S. M., Verweij, K. J. H., Krueger, R. F., Luciano, M., Arias Vasquez, A., Matteson, L. K., Derringer, J., Esko, T., Amin, N., Gordon, S. D., Hansell, N. K., Hart, A. B., Seppälä, I., Huffman, J. E., Konte, B., Lahti, J., Lee, M., Miller, M., Nutile, T., Tanaka, T., Teumer, A., Viktorin, A., Wedenoja, J., Abecasis, G. R., Adkins, D. E., Agrawal, A., Allik, J., Appel, K., Bigdeli, T. B., Busonero, F., Campbell, H., Costa, P. T., Davey Smith, G., Davies, G., de Wit, H., Ding, J., Engelhardt, B. E., Eriksson, J. G., Fedko, I. O., Ferrucci, L., Franke, B., Giegling, I., Grucza, R., Hartmann, A. M., Heath, A. C., Heinonen, K., Henders, A. K., Homuth, G., Hottenga, J.-J., Iacono, W. G., Janzing, J., Jokela, M., Karlsson, R., Kemp, J. P., Kirkpatrick, M. G., Latvala, A., Lehtimäki, T., Liewald, D. C., Madden, P. A. F., Magri, C., Magnusson, P. K. E., Marten, J., Maschio, A., Medland, S. E., Mihailov, E., Milaneschi, Y., Montgomery, G. W., Nauck, M., Ouwens, K. G., Palotie, A., Pettersson, E., Polasek, O., Qian, Y., Pulkki-Råback, L., Raitakari, O. T., Realo, A., Rose, R. J., Ruggiero, D., Schmidt, C. O., Slutske, W. S., Sorice, R., Starr, J. M., St Pourcain, B., Sutin, A. R., Timpson, N. J., Trochet, H., Vermeulen, S., Vuoksimaa, E., Widen, E., Wouda, J., Wright, M. J., Zgaga, L., Porteous, D., Minelli, A., Palmer, A. A., Rujescu, D., Ciullo, M., Hayward, C., Rudan, I., Metspalu, A., Kaprio, J., Deary, I. J., Räikkönen, K., Wilson, J. F., Keltikangas-Järvinen, L., Bierut, L. J., Hettema, J. M., Grabe, H. J., van Duijn, C. M., Evans, D. M., Schlessinger, D., Pedersen, N. L., Terracciano, A., McGue, M., Penninx, B. W. J. H., Martin, N. G., & Boomsma, D. I.
- Affiliations
- 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
- Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands
- QIMR Berghofer Medical Research Institute (AU)
- University of Minnesota (US)
- Centre for Cognitive Ageing and Cognitive Epidemiology, University of Edinburgh, Edinburgh, Scotland9Department of Psychology, University of Edinburgh, Edinburgh, Scotland
- 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
- University of Illinois Urbana-Champaign (US)
- University of Tartu (EE)
- Erasmus MC (NL)
- University of Chicago (US)
- Fimlab (Finland) (FI)
- Western General Hospital (GB)
- Martin Luther University Halle-Wittenberg (DE)
- University of Helsinki (FI)
- Virginia Commonwealth University (US)
- Institute of Genetics and Biophysics (IT)
- National Institutes of Health (US)
- Universitätsmedizin Greifswald (DE)
- Karolinska Institutet (SE)
- Center for Statistical Genetics, Department of Biostatistics, University of Michigan School of Public Health, Ann Arbor
- Department of Psychiatry, Washington University School of Medicine, St Louis, Missouri
- Department of Psychology, University of Tartu, Tartu, Estonia33Estonian Academy of Sciences, Tallinn, Estonia
- Institute of Genetic and Biomedical Research (IT)
- University of Edinburgh (GB)
- Duke University (US)
- Medical Research Council Integrative Epidemiology Unit, School of Social and Community Medicine, University of Bristol, Bristol, England
- Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois
- Princeton University (US)
- Vrije Universiteit Amsterdam (NL)
- Radboud University Nijmegen (NL)
- Washington University in St. Louis (US)
- Universität Greifswald (DE)
- Translational Research Institute (AU)
- University of Brescia (IT)
- Amsterdam Neuroscience (NL)
- Department of Public Health, Faculty of Medicine, University of Split, Split, Croatia
- Institute of Behavioural Sciences, University of Helsinki, Helsinki, Finland
- University of Turku (FI)
- Indiana University Bloomington (US)
- University of Missouri (US)
- Alzheimer Scotland (GB)
- 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
- Florida State University (US)
- University of Bristol (GB)
- Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland
- Trinity College Dublin (IE)
- Estonian Academy of Sciences (EE)
- Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands
- ORCID
- Verweij, Karin J. H.
- Derringer, Jaime
- Esko, Tõnu
- Amin, Najaf
- Gordon, Scott D.
- Hansell, Narelle K.
- Seppälä, Ilkka
- Huffman, Jennifer E.
- Konte, Bettina
- Lahti, Jari
- Lee, Minyoung
- Nutile, Teresa
- Teumer, Alexander
- Viktorin, Alexander
- Wedenoja, Juho
- Adkins, Daniel E.
- Busonero, Fabio
- Costa, Paul T.
- Davies, Gail
- Ding, Jun
- Engelhardt, Barbara E.
- Eriksson, Johan G.
- Fedko, Iryna O.
- Ferrucci, Luigi
- Franke, Barbara
- Giegling, Ina
- Grucza, Richard
- Hartmann, Annette M.
- Heath, Andrew C.
- Heinonen, Kati
- Henders, Anjali K.
- Homuth, Georg
- Hottenga, Jouke-Jan
- Iacono, William G.
- Janzing, Joost
- Jokela, Markus
- Karlsson, Robert
- Kemp, John P.
- Kirkpatrick, Matthew G.
- Latvala, Antti
- Lehtimäki, Terho
- Liewald, David C.
- Madden, Pamela A. F.
- Magri, Chiara
- Magnusson, Patrik K. E.
- Marten, Jonathan
- Maschio, Andrea
- Medland, Sarah E.
- Milaneschi, Yuri
- Montgomery, Grant W.
- Nauck, Matthias
- Ouwens, Klaasjan G.
- Palotie, Aarno
- Pettersson, Erik
- Qian, Yong
- Raitakari, Olli T.
- Realo, Anu
- Rose, Richard J.
- Ruggiero, Daniela
- Schmidt, Carsten O.
- Slutske, Wendy S.
- Starr, John M.
- Sutin, Angelina R.
- Timpson, Nicholas J.
- Trochet, Holly
- Vermeulen, Sita
- Vuoksimaa, Eero
- Wright, Margaret J.
- Zgaga, Lina
- Porteous, David
- Minelli, Alessandra
- Palmer, Abraham A.
- Rujescu, Dan
- Ciullo, Marina
- Hayward, Caroline
- Rudan, Igor
- Metspalu, Andres
- Kaprio, Jaakko
- Deary, Ian J.
- Räikkönen, Katri
- Wilson, James F.
- Bierut, Laura J.
- Hettema, John M.
- Grabe, Hans J.
- Evans, David M.
- Pedersen, Nancy L.
- Terracciano, Antonio
- McGue, Matt
- Penninx, Brenda W. J. H.
- Martin, Nicholas G.
- Boomsma, Dorret I.
- Venue
- JAMA Psychiatry
- Publisher
- American Medical Association (AMA)
- Published
- 2015-07-01
- Volume
- 72
- Issue
- 7
- Pages
- 642
- ISSN
- 2168-622X (ISSN-L)
- PMC
- PMC4667957
- OpenAlex
- W1914301979
- Cited by
- 345
- References
- 71
- Citations by year
- 2026: 3 · 2025: 13 · 2024: 40 · 2023: 20 · 2022: 16 · 2021: 14 · 2020: 66 · 2019: 28 · 2018: 43 · 2017: 45 · 2016: 45 · 2015: 12
- FWCI
- 6.33
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- JAMA Psychiatry (publishedVersion)
- PubMed (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- Explore Bristol Research (publishedVersion)
- University of Twente Research Information (publishedVersion, other-oa)
- University of Southern Denmark Research Portal (University of Southern Denmark) (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Pure Amsterdam UMC (submittedVersion, cc-by)
- Radboud Repository (Radboud University) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Institutional Research Information System (Università degli Studi di Brescia) (submittedVersion, other-oa)
- MPG.PuRe (Max Planck Society) (submittedVersion)
- VU Research Portal (submittedVersion)
- STM:n Hallinnonalan avoin julkaisuarkisto (Julkari) (submittedVersion)
- University of Twente Research Information (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Funders
- Florida State University
- Princeton University
- University of Missouri
- University of Minnesota
- Helsingin Yliopisto
- Eesti Teaduste Akadeemia
- Virginia Commonwealth University
- Wellcome Trust (076467/Z/05/Z, 102215, 104036)
- School of Public Health, University of Michigan
- QIMR Berghofer Medical Research Institute
- University of Bristol
- Trinity College Dublin
- ZonMw (91111025)
- Radboud Universiteit
- Vrije Universiteit Amsterdam
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek (480- 05-003, 904-61-193, 904-61-090, 047.017.043, 480-04-004, 575-25-006)
- 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 (5u01da024417-02, 1r01mh081802-01)
- University of Illinois at Urbana-Champaign
- School of Medicine, Duke University
- Medical Research Council (MR/K026992/1, MC_PC_15018)
- Biotechnology and Biological Sciences Research Council (BB/F019394/1)
- Erasmus Universitair Medisch Centrum Rotterdam
- Diamantina Institute, University of Queensland
- National Institute on Alcohol Abuse and Alcoholism (R01AA009367, K02AA018755, R37AA007728, K05AA000145, R01AA013321, P50AA011998, R01AA012502, R01AA007728, T32AA007580, R01AA009203, R01AA013320, R37AA012502, R01AA015416, R01AA011886, U10AA008401)
- National Institute of Mental Health (U01MH046276, R01MH059566, U01MH046318, R01MH059571, R01MH060879, R01MH059565, R01MH060870, U01MH046289, U01MH079469, R01MH061675, R01MH059586, R01MH066140, R01MH059588, R01MH067257, U01MH079470, R01MH066206, RC2MH089951, R01 MH081802, R01MH059587, T32MH016880)
- National Institute on Drug Abuse (U01-DA024417, R56DA012854, R21DA024845, R01DA013240, K08DA019951, R01DA021336, R01DA024417, R01DA036216, R37DA005147, R01DA002812, R01DA012854, T32DA007255)
- National Human Genome Research Institute (U01HG004422, R00HG006265, U01HG004446, U01HG004438, HHSN268200782096C, K99HG006265)
- National Cancer Institute (P01CA089392)
- Institute of Genetics
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Keywords
- neuroticism, major depressive disorder, personality traits, MAGI1, heritability, polygenic risk score, genetic risk prediction, psychiatric genetics, personality genetics, bipolar disorder, schizophrenia, single nucleotide polymorphisms, replication failure
- MeSH terms
- Neuroticism, Anxiety Disorders, Major Depressive Disorder, Humans, Personality, Risk Factors, Cell Adhesion Molecules, Cell Adhesion Molecules, Neuronal, Genetic Predisposition to Disease, Multifactorial Inheritance, Polymorphism, Single Nucleotide, Adaptor Proteins, Signal Transducing, Guanylate Kinases, Genome-Wide Association Study
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