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

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Résumé

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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La notice

Revue

JAMA Psychiatry

Thématique

Genetic Associations and Epidemiology

Domaine

Biochemistry, Genetics and Molecular Biology

Établissements canadiens

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Organismes subventionnaires

National Human Genome Research InstituteNational Institute on Drug AbuseDiamantina Institute, University of QueenslandErasmus Universitair Medisch Centrum RotterdamMedical Research CouncilNational Institutes of HealthUniversität GreifswaldCentre for Cognitive Ageing and Cognitive EpidemiologyUniversity of Illinois at Urbana-ChampaignTerveyden ja hyvinvoinnin laitosTurun Yliopistollinen KeskussairaalaUniversity of MinnesotaUniversità degli Studi di BresciaNational Institute of Mental HealthQIMR Berghofer Medical Research InstituteTurun YliopistoNational Institute on Alcohol Abuse and AlcoholismSamfundet FolkhälsanVrije Universiteit AmsterdamRadboud Universitair Medisch CentrumTrinity College DublinNational Cancer InstituteUniversity of BristolSchool of Public Health, University of MichiganNederlandse Organisatie voor Wetenschappelijk OnderzoekBiotechnology and Biological Sciences Research CouncilWellcome TrustTampereen YliopistoRadboud UniversiteitEesti Teaduste AkadeemiaSchool of Medicine, Duke UniversityUniversity of MissouriHelsingin YliopistoFlorida State UniversityZonMwKarolinska InstitutetInstitute of GeneticsTartu ÜlikoolPrinceton UniversityVirginia Commonwealth University

Mots-clés

Genome-wide association studyNeuroticismMajor depressive disorderSingle-nucleotide polymorphismGenetic associationMeta-analysisGeneticsHeritabilityImputation (statistics)SNPBiologyPersonalityPsychologyMedicineClinical psychologyGenotypeMoodInternal medicineGeneMissing data

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