Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder

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

doi:10.1001/jamapsychiatry.2015.0554

Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder

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

^*Corresponding author for this work

Department of Clinical Child and Family Studies
Vrije Universiteit Amsterdam
Department of Methods
Department of Biological Psychology
Department of Research Methodology
University of Twente
Department of Developmental Psychology
University of Amsterdam
Queensland Institute of Medical Research
Department of Psychology
University of Minnesota Twin Cities
University of Edinburgh
Department of Psychology
Department of Cognitive Neuroscience
Radboud University Nijmegen
Department of Psychiatry
Department of Human Genetics
Department of Psychology
University of Illinois at Urbana-Champaign
University of Tartu
Department of Epidemiology
Erasmus University Rotterdam
Department of Human Genetics
The University of Chicago
Department of Clinical Chemistry
Fimlab Laboratories
Department of Psychiatry
Martin Luther University Halle-Wittenberg
Folkhalsan
Institute of Behavioural Sciences
University of Helsinki
Virginia Commonwealth University
Virginia Commonwealth University
National Research Council of Italy
National Institutes of Health
Institute for Community Medicine
University of Greifswald
Department of Medical Epidemiology and Biostatistics
Karolinska Institutet
Department of Public Health
Department of Biostatistics and Center for Statistics Genetics
University of Michigan, Ann Arbor
Department of Pharmacotherapy and Outcomes Science
Department of Psychiatry
Washington University St. Louis
Department of Psychology
University of Tartu
Estonian Academy of Sciences
Department of Psychiatry and Psychotherapy
Institute for Population Health Sciences and Informatics
Duke University
University of Bristol
Department of Psychiatry and Behavioral Neuroscience
Princeton University
Department of General Practice and Primary Health Care
Vaasa Hospital District
National Institute for Health and Welfare
Interfaculty Institute for Genetics and Functional Genomics
University of Queensland
Department of Molecular and Translational Medicine
University of Brescia
Department of Biotechnology
Department of Psychiatry
VU University Medical Center
Institute of Clinical Chemistry and Laboratory Medicine
Wellcome Trust
University of Split
Department of Clinical Physiology and Nuclear Medicine
University of Turku
Department of Psychological and Brain Sciences
Indiana University Bloomington
Department of Psychological Sciences
University of Missouri
School of Experimental Psychology
Florida State University
Department for Health Evidence
Department of Public Health and Primary Care
Trinity College Dublin
Medical Genetics Section
HELIOS-Hospital Stralsund
University of Southern Denmark
Department of Psychiatry and Psychotherapy

Research output: Contribution to journal › Article › peer-review

229 Citations (Scopus)

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.

Original language	English
Pages (from-to)	642-650
Number of pages	9
Journal	JAMA Psychiatry
Volume	72
Issue number	7
DOIs	https://doi.org/10.1001/jamapsychiatry.2015.0554
Publication status	Published - 1 Jul 2015
Externally published	Yes

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10.1001/jamapsychiatry.2015.0554

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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., ... Boomsma, D. I. (2015). Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder. JAMA Psychiatry, 72(7), 642-650. https://doi.org/10.1001/jamapsychiatry.2015.0554

@article{7d00f5b6166e446ea2602b61fbca5eb3,

title = "Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder",

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 {\texttimes} 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 {\texttimes} 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 {\texttimes} 10-12 < P <.05) and MDD (4.02 {\texttimes} 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.",

author = "\{De Moor\}, \{Marleen H.M.\} and \{Van Den Berg\}, \{St{\'e}phanie M.\} and Verweij, \{Karin J.H.\} and Krueger, \{Robert F.\} and Michelle Luciano and \{Arias Vasquez\}, Alejandro and Matteson, \{Lindsay K.\} and Jaime Derringer and T{\~o}nu Esko and Najaf Amin and Gordon, \{Scott D.\} and Hansell, \{Narelle K.\} and Hart, \{Amy B.\} and Ilkka Sepp{\"a}l{\"a} and Huffman, \{Jennifer E.\} and Bettina Konte and Jari Lahti and Minyoung Lee and Mike Miller and Teresa Nutile and Toshiko Tanaka and Alexander Teumer and Alexander Viktorin and Juho Wedenoja and Abecasis, \{Goncalo R.\} and Adkins, \{Daniel E.\} and Arpana Agrawal and J{\"u}ri Allik and Katja Appel and Bigdeli, \{Timothy B.\} and Fabio Busonero and Harry Campbell and Costa, \{Paul T.\} and \{Davey Smith\}, George and Gail Davies and \{De Wit\}, Harriet and Jun Ding and Engelhardt, \{Barbara E.\} and Eriksson, \{Johan G.\} and Fedko, \{Iryna O.\} and Luigi Ferrucci and Barbara Franke and Ina Giegling and Richard Grucza and Hartmann, \{Annette M.\} and Heath, \{Andrew C.\} and Kati Heinonen and Henders, \{Anjali K.\} and Georg Homuth and Hottenga, \{Jouke Jan\} and Iacono, \{William G.\} and Joost Janzing and Markus Jokela and Robert Karlsson and Kemp, \{John P.\} and Kirkpatrick, \{Matthew G.\} and Antti Latvala and Terho Lehtim{\"a}ki and Liewald, \{David C.\} and Madden, \{Pamela A.F.\} and Chiara Magri and Magnusson, \{Patrik K.E.\} and Jonathan Marten and Andrea Maschio and Medland, \{Sarah E.\} and Evelin Mihailov and Yuri Milaneschi and Montgomery, \{Grant W.\} and Matthias Nauck and Ouwens, \{Klaasjan G.\} and Aarno Palotie and Erik Pettersson and Ozren Polasek and Yong Qian and Laura Pulkki-R{\aa}back and Raitakari, \{Olli T.\} and Anu Realo and Rose, \{Richard J.\} and Daniela Ruggiero and Schmidt, \{Carsten O.\} and Slutske, \{Wendy S.\} and Rossella Sorice and Starr, \{John M.\} and \{St Pourcain\}, Beate and Sutin, \{Angelina R.\} and Timpson, \{Nicholas J.\} and Holly Trochet and Sita Vermeulen and Eero Vuoksimaa and Elisabeth Widen and Jasper Wouda and Wright, \{Margaret J.\} and Lina Zgaga and David Porteous and Alessandra Minelli and Palmer, \{Abraham A.\} and Dan Rujescu and Marina Ciullo and Caroline Hayward and Igor Rudan and Andres Metspalu and Jaakko Kaprio and Deary, \{Ian J.\} and Katri R{\"a}ikk{\"o}nen and Wilson, \{James F.\} and Liisa Keltikangas-J{\"a}rvinen and Bierut, \{Laura J.\} and Hettema, \{John M.\} and Grabe, \{Hans J.\} and \{Van Duijn\}, \{Cornelia M.\} and Evans, \{David M.\} and David Schlessinger and Pedersen, \{Nancy L.\} and Antonio Terracciano and Matt McGue and Penninx, \{Brenda W.J.H.\} and Martin, \{Nicholas G.\} and Boomsma, \{Dorret I.\}",

year = "2015",

month = jul,

day = "1",

doi = "10.1001/jamapsychiatry.2015.0554",

language = "English",

volume = "72",

pages = "642--650",

journal = "JAMA Psychiatry",

issn = "2168-622X",

number = "7",

}

De Moor, MHM, Van Den Berg, SM, Verweij, KJH, Krueger, RF, Luciano, M, Arias Vasquez, A, Matteson, LK, Derringer, J, Esko, T, Amin, N, Gordon, SD, Hansell, NK, Hart, AB, Seppälä, I, Huffman, JE, Konte, B, Lahti, J, Lee, M, Miller, M, Nutile, T, Tanaka, T, Teumer, A, Viktorin, A, Wedenoja, J, Abecasis, GR, Adkins, DE, Agrawal, A, Allik, J, Appel, K, Bigdeli, TB, Busonero, F, Campbell, H, Costa, PT, Davey Smith, G, Davies, G, De Wit, H, Ding, J, Engelhardt, BE, Eriksson, JG, Fedko, IO, Ferrucci, L, Franke, B, Giegling, I, Grucza, R, Hartmann, AM, Heath, AC, Heinonen, K, Henders, AK, Homuth, G, Hottenga, JJ, Iacono, WG, Janzing, J, Jokela, M, Karlsson, R, Kemp, JP, Kirkpatrick, MG, Latvala, A, Lehtimäki, T, Liewald, DC, Madden, PAF, Magri, C, Magnusson, PKE, Marten, J, Maschio, A, Medland, SE, Mihailov, E, Milaneschi, Y, Montgomery, GW, Nauck, M, Ouwens, KG, Palotie, A, Pettersson, E, Polasek, O, Qian, Y, Pulkki-Råback, L, Raitakari, OT, Realo, A, Rose, RJ, Ruggiero, D, Schmidt, CO, Slutske, WS, Sorice, R, Starr, JM, St Pourcain, B, Sutin, AR, Timpson, NJ, Trochet, H, Vermeulen, S, Vuoksimaa, E, Widen, E, Wouda, J, Wright, MJ, Zgaga, L, Porteous, D, Minelli, A, Palmer, AA, Rujescu, D, Ciullo, M, Hayward, C, Rudan, I, Metspalu, A, Kaprio, J, Deary, IJ, Räikkönen, K, Wilson, JF, Keltikangas-Järvinen, L, Bierut, LJ, Hettema, JM, Grabe, HJ, Van Duijn, CM, Evans, DM, Schlessinger, D, Pedersen, NL, Terracciano, A, McGue, M, Penninx, BWJH, Martin, NG & Boomsma, DI 2015, 'Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder', JAMA Psychiatry, vol. 72, no. 7, pp. 642-650. https://doi.org/10.1001/jamapsychiatry.2015.0554

TY - JOUR

T1 - Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder

AU - De Moor, Marleen H.M.

AU - Van Den Berg, Stéphanie M.

AU - Verweij, Karin J.H.

AU - Krueger, Robert F.

AU - Luciano, Michelle

AU - Arias Vasquez, Alejandro

AU - Matteson, Lindsay K.

AU - Derringer, Jaime

AU - Esko, Tõnu

AU - Amin, Najaf

AU - Gordon, Scott D.

AU - Hansell, Narelle K.

AU - Hart, Amy B.

AU - Seppälä, Ilkka

AU - Huffman, Jennifer E.

AU - Konte, Bettina

AU - Lahti, Jari

AU - Lee, Minyoung

AU - Miller, Mike

AU - Nutile, Teresa

AU - Tanaka, Toshiko

AU - Teumer, Alexander

AU - Viktorin, Alexander

AU - Wedenoja, Juho

AU - Abecasis, Goncalo R.

AU - Adkins, Daniel E.

AU - Agrawal, Arpana

AU - Allik, Jüri

AU - Appel, Katja

AU - Bigdeli, Timothy B.

AU - Busonero, Fabio

AU - Campbell, Harry

AU - Costa, Paul T.

AU - Davey Smith, George

AU - Davies, Gail

AU - De Wit, Harriet

AU - Ding, Jun

AU - Engelhardt, Barbara E.

AU - Eriksson, Johan G.

AU - Fedko, Iryna O.

AU - Ferrucci, Luigi

AU - Franke, Barbara

AU - Giegling, Ina

AU - Grucza, Richard

AU - Hartmann, Annette M.

AU - Heath, Andrew C.

AU - Heinonen, Kati

AU - Henders, Anjali K.

AU - Homuth, Georg

AU - Hottenga, Jouke Jan

AU - Iacono, William G.

AU - Janzing, Joost

AU - Jokela, Markus

AU - Karlsson, Robert

AU - Kemp, John P.

AU - Kirkpatrick, Matthew G.

AU - Latvala, Antti

AU - Lehtimäki, Terho

AU - Liewald, David C.

AU - Madden, Pamela A.F.

AU - Magri, Chiara

AU - Magnusson, Patrik K.E.

AU - Marten, Jonathan

AU - Maschio, Andrea

AU - Medland, Sarah E.

AU - Mihailov, Evelin

AU - Milaneschi, Yuri

AU - Montgomery, Grant W.

AU - Nauck, Matthias

AU - Ouwens, Klaasjan G.

AU - Palotie, Aarno

AU - Pettersson, Erik

AU - Polasek, Ozren

AU - Qian, Yong

AU - Pulkki-Råback, Laura

AU - Raitakari, Olli T.

AU - Realo, Anu

AU - Rose, Richard J.

AU - Ruggiero, Daniela

AU - Schmidt, Carsten O.

AU - Slutske, Wendy S.

AU - Sorice, Rossella

AU - Starr, John M.

AU - St Pourcain, Beate

AU - Sutin, Angelina R.

AU - Timpson, Nicholas J.

AU - Trochet, Holly

AU - Vermeulen, Sita

AU - Vuoksimaa, Eero

AU - Widen, Elisabeth

AU - Wouda, Jasper

AU - Wright, Margaret J.

AU - Zgaga, Lina

AU - Porteous, David

AU - Minelli, Alessandra

AU - Palmer, Abraham A.

AU - Rujescu, Dan

AU - Ciullo, Marina

AU - Hayward, Caroline

AU - Rudan, Igor

AU - Metspalu, Andres

AU - Kaprio, Jaakko

AU - Deary, Ian J.

AU - Räikkönen, Katri

AU - Wilson, James F.

AU - Keltikangas-Järvinen, Liisa

AU - Bierut, Laura J.

AU - Hettema, John M.

AU - Grabe, Hans J.

AU - Van Duijn, Cornelia M.

AU - Evans, David M.

AU - Schlessinger, David

AU - Pedersen, Nancy L.

AU - Terracciano, Antonio

AU - McGue, Matt

AU - Penninx, Brenda W.J.H.

AU - Martin, Nicholas G.

AU - Boomsma, Dorret I.

PY - 2015/7/1

Y1 - 2015/7/1

N2 - 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.

AB - 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.

UR - https://www.scopus.com/pages/publications/84937399367

U2 - 10.1001/jamapsychiatry.2015.0554

DO - 10.1001/jamapsychiatry.2015.0554

M3 - Article

C2 - 25993607

AN - SCOPUS:84937399367

SN - 2168-622X

VL - 72

SP - 642

EP - 650

JO - JAMA Psychiatry

JF - JAMA Psychiatry

IS - 7

ER -

Meta-analysis of genome-wide association studies for neuroticism, and the polygenic association with major depressive disorder

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