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

Importance Neuroticismis 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 neuroticismby 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 variationin neuroticismby estimating SNP-based heritability; and to examine whether SNPs that predict neuroticismalso predict MDD. Design, Setting, and Participants Genome-wide association meta-analysis of 30 cohortswith genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63 661 participants from 29 discovery cohortsand 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 Neuroticismscores harmonized across all 29 discovery cohortsby item response theoryanalysis, 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. Polygenicscores based on the meta-analysis of neuroticismin 27 cohortssignificantly 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 neuroticismis 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 neuroticismand further investigate the association of MAGI1 and the polygenicassociation to a range of other psychiatric disorders that are phenotypically correlated with neuroticism