Marleen H M de Moor1, Stéphanie M van den Berg2, Karin J H Verweij3, Robert F Krueger4, Michelle Luciano5, Alejandro Arias Vasquez6, Lindsay K Matteson4, Jaime Derringer7, Tõnu Esko8, Najaf Amin9, Scott D Gordon10, Narelle K Hansell10, Amy B Hart11, Ilkka Seppälä12, Jennifer E Huffman13, Bettina Konte14, Jari Lahti15, Minyoung Lee16, Mike Miller4, Teresa Nutile17, Toshiko Tanaka18, Alexander Teumer19, Alexander Viktorin20, Juho Wedenoja21, Goncalo R Abecasis22, Daniel E Adkins23, Arpana Agrawal24, Jüri Allik25, Katja Appel26, Timothy B Bigdeli16, Fabio Busonero27, Harry Campbell28, Paul T Costa29, George Davey Smith30, Gail Davies5, Harriet de Wit31, Jun Ding18, Barbara E Engelhardt32, Johan G Eriksson33, Iryna O Fedko34, Luigi Ferrucci18, Barbara Franke35, Ina Giegling14, Richard Grucza24, Annette M Hartmann14, Andrew C Heath24, Kati Heinonen36, Anjali K Henders10, Georg Homuth37, Jouke-Jan Hottenga34, William G Iacono4, Joost Janzing38, Markus Jokela36, Robert Karlsson20, John P Kemp39, Matthew G Kirkpatrick31, Antti Latvala40, Terho Lehtimäki12, David C Liewald5, Pamela A F Madden24, Chiara Magri41, Patrik K E Magnusson20, Jonathan Marten13, Andrea Maschio27, Sarah E Medland10, Evelin Mihailov42, Yuri Milaneschi43, Grant W Montgomery10, Matthias Nauck44, Klaasjan G Ouwens34, Aarno Palotie45, Erik Pettersson20, Ozren Polasek46, Yong Qian18, Laura Pulkki-Råback36, Olli T Raitakari47, Anu Realo48, Richard J Rose49, Daniela Ruggiero17, Carsten O Schmidt19, Wendy S Slutske50, Rossella Sorice17, John M Starr51, Beate St Pourcain52, Angelina R Sutin53, Nicholas J Timpson30, Holly Trochet13, Sita Vermeulen54, Eero Vuoksimaa21, Elisabeth Widen55, Jasper Wouda56, Margaret J Wright10, Lina Zgaga57, David Porteous58, Alessandra Minelli41, Abraham A Palmer59, Dan Rujescu14, Marina Ciullo17, Caroline Hayward60, Igor Rudan28, Andres Metspalu61, Jaakko Kaprio62, Ian J Deary5, Katri Räikkönen36, James F Wilson28, Liisa Keltikangas-Järvinen36, Laura J Bierut24, John M Hettema16, Hans J Grabe63, Cornelia M van Duijn9, David M Evans39, David Schlessinger18, Nancy L Pedersen17, Antonio Terracciano64, Matt McGue65, Brenda W J H Penninx43, Nicholas G Martin10, Dorret I Boomsma34. 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.
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.
Authors: Gitta H Lubke; Jouke Jan Hottenga; Raymond Walters; Charles Laurin; Eco J C de Geus; Gonneke Willemsen; Jan H Smit; Christel M Middeldorp; Brenda W J H Penninx; Jacqueline M Vink; Dorret I Boomsma Journal: Biol Psychiatry Date: 2012-04-19 Impact factor: 13.382
Authors: Danielle R Miller; Mark W Logue; Erika J Wolf; Hannah Maniates; Meghan E Robinson; Jasmeet P Hayes; Annjanette Stone; Steven Schichman; Regina E McGlinchey; William P Milberg; Mark W Miller Journal: Depress Anxiety Date: 2017-05-11 Impact factor: 6.505
Authors: Benjamin B Lahey; Robert F Krueger; Paul J Rathouz; Irwin D Waldman; David H Zald Journal: Psychol Bull Date: 2016-12-22 Impact factor: 17.737
Authors: Jun-Ichi Abe; Kyung Ae Ko; Sivareddy Kotla; Yin Wang; Jesus Paez-Mayorga; Ik Jae Shin; Masaki Imanishi; Hang Thi Vu; Yunting Tao; Miguel M Leiva-Juarez; Tamlyn N Thomas; Jan L Medina; Jong Hak Won; Yuka Fujii; Carolyn J Giancursio; Elena McBeath; Ji-Hyun Shin; Liliana Guzman; Rei J Abe; Jack Taunton; Naoki Mochizuki; William Faubion; John P Cooke; Keigi Fujiwara; Scott E Evans; Nhat-Tu Le Journal: JCI Insight Date: 2019-04-04
Authors: Minyoung Lee; Steven H Aggen; Takeshi Otowa; Enrique Castelao; Martin Preisig; Hans J Grabe; Catharina A Hartman; Albertine J Oldehinkel; Christel M Middeldorp; Henning Tiemeier; John M Hettema Journal: Int J Methods Psychiatr Res Date: 2016-07-15 Impact factor: 4.035
Authors: Abdel Abdellaoui; Hsi-Yuan Chen; Gonneke Willemsen; Erik A Ehli; Gareth E Davies; Karin J H Verweij; Michel G Nivard; Eco J C de Geus; Dorret I Boomsma; John T Cacioppo Journal: J Pers Date: 2018-08-02