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Meta-Analysis
, 72 (7), 642-50

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

Genetics of Personality ConsortiumMarleen H M de Moor  1 Stéphanie M van den Berg  2 Karin J H Verweij  3 Robert F Krueger  4 Michelle Luciano  5 Alejandro Arias Vasquez  6 Lindsay K Matteson  4 Jaime Derringer  7 Tõnu Esko  8 Najaf Amin  9 Scott D Gordon  10 Narelle K Hansell  10 Amy B Hart  11 Ilkka Seppälä  12 Jennifer E Huffman  13 Bettina Konte  14 Jari Lahti  15 Minyoung Lee  16 Mike Miller  4 Teresa Nutile  17 Toshiko Tanaka  18 Alexander Teumer  19 Alexander Viktorin  20 Juho Wedenoja  21 Goncalo R Abecasis  22 Daniel E Adkins  23 Arpana Agrawal  24 Jüri Allik  25 Katja Appel  26 Timothy B Bigdeli  16 Fabio Busonero  27 Harry Campbell  28 Paul T Costa  29 George Davey Smith  30 Gail Davies  5 Harriet de Wit  31 Jun Ding  18 Barbara E Engelhardt  32 Johan G Eriksson  33 Iryna O Fedko  34 Luigi Ferrucci  18 Barbara Franke  35 Ina Giegling  14 Richard Grucza  24 Annette M Hartmann  14 Andrew C Heath  24 Kati Heinonen  36 Anjali K Henders  10 Georg Homuth  37 Jouke-Jan Hottenga  34 William G Iacono  4 Joost Janzing  38 Markus Jokela  36 Robert Karlsson  20 John P Kemp  39 Matthew G Kirkpatrick  31 Antti Latvala  40 Terho Lehtimäki  12 David C Liewald  5 Pamela A F Madden  24 Chiara Magri  41 Patrik K E Magnusson  20 Jonathan Marten  13 Andrea Maschio  27 Sarah E Medland  10 Evelin Mihailov  42 Yuri Milaneschi  43 Grant W Montgomery  10 Matthias Nauck  44 Klaasjan G Ouwens  34 Aarno Palotie  45 Erik Pettersson  20 Ozren Polasek  46 Yong Qian  18 Laura Pulkki-Råback  36 Olli T Raitakari  47 Anu Realo  48 Richard J Rose  49 Daniela Ruggiero  17 Carsten O Schmidt  19 Wendy S Slutske  50 Rossella Sorice  17 John M Starr  51 Beate St Pourcain  52 Angelina R Sutin  53 Nicholas J Timpson  30 Holly Trochet  13 Sita Vermeulen  54 Eero Vuoksimaa  21 Elisabeth Widen  55 Jasper Wouda  56 Margaret J Wright  10 Lina Zgaga  57 David Porteous  58 Alessandra Minelli  41 Abraham A Palmer  59 Dan Rujescu  14 Marina Ciullo  17 Caroline Hayward  60 Igor Rudan  28 Andres Metspalu  61 Jaakko Kaprio  62 Ian J Deary  5 Katri Räikkönen  36 James F Wilson  28 Liisa Keltikangas-Järvinen  36 Laura J Bierut  24 John M Hettema  16 Hans J Grabe  63 Cornelia M van Duijn  9 David M Evans  39 David Schlessinger  18 Nancy L Pedersen  17 Antonio Terracciano  64 Matt McGue  65 Brenda W J H Penninx  43 Nicholas G Martin  10 Dorret I Boomsma  34
Affiliations
Meta-Analysis

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

Genetics of Personality Consortium et al. JAMA Psychiatry.

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.

Conflict of interest statement

Conflict of interest disclosures: there is no conflict of interest.

Figures

Figure 1
Figure 1
Region plot for genome-wide significant SNP rs35855737 in the MAGI1 gene on chromosome 3 for neuroticism
Figure 2
Figure 2
Forest plot for genome-wide significant SNP rs35855737 in the MAGI1 gene on chromosome 3 for neuroticism
Figure 3
Figure 3
Manhattan plot for meta-analysis results for neuroticism in 29 discovery cohorts
Figure 4
Figure 4
Quantile-quantile plots for meta-analysis results for neuroticism in 29 discovery cohorts
Figure 5
Figure 5
Results of polygenic risk score analyses predicting MDD and neuroticism based on neuroticism polygenic risk scores Note: Prediction of neuroticism and MDD in NTR/NESDA cohorts based on neuroticism polygenic risk scores from meta-analysis results omitting NTR/NESDA cohorts significant with *P<0.05 or ** P<0.001. Different colored bars refer to different P-value thresholds used to calculate the polygenic risk scores.

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