Meta-analysis of Genome-wide Association Studies for Neuroticism, and the Polygenic Association With Major Depressive Disorder.
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- Authors
- Genetics of Personality Consortium; de Moor, Marleen H M; van den Berg, StΓ©phanie M; Verweij, Karin J H; Krueger, Robert F; Luciano, Michelle; Arias Vasquez, Alejandro; Matteson, Lindsay K; Derringer, Jaime; Esko, TΓ΅nu; Amin, Najaf; Gordon, Scott D; Hansell, Narelle K; Hart, Amy B; SeppΓ€lΓ€, Ilkka; Huffman, Jennifer E; Konte, Bettina; Lahti, Jari; Lee, Minyoung; Miller, Mike; Nutile, Teresa; Tanaka, Toshiko; Teumer, Alexander; Viktorin, Alexander; Wedenoja, Juho; Abecasis, Goncalo R; Adkins, Daniel E; Agrawal, Arpana; Allik, JΓΌri; Appel, Katja; Bigdeli, Timothy B; Busonero, Fabio; Campbell, Harry; Costa, Paul T; Davey Smith, George; Davies, Gail; de Wit, Harriet; Ding, Jun; Engelhardt, Barbara E; Eriksson, Johan G; Fedko, Iryna O; Ferrucci, Luigi; Franke, Barbara; Giegling, Ina; Grucza, Richard; Hartmann, Annette M; Heath, Andrew C; Heinonen, Kati; Henders, Anjali K; Homuth, Georg; Hottenga, Jouke-Jan; Iacono, William G; Janzing, Joost; Jokela, Markus; Karlsson, Robert; Kemp, John P; Kirkpatrick, Matthew G; Latvala, Antti; LehtimΓ€ki, Terho; Liewald, David C; Madden, Pamela A F; Magri, Chiara; Magnusson, Patrik K E; Marten, Jonathan; Maschio, Andrea; Medland, Sarah E; Mihailov, Evelin; Milaneschi, Yuri; Montgomery, Grant W; Nauck, Matthias; Ouwens, Klaasjan G; Palotie, Aarno; Pettersson, Erik; Polasek, Ozren; Qian, Yong; Pulkki-RΓ₯back, Laura; Raitakari, Olli T; Realo, Anu; Rose, Richard J; Ruggiero, Daniela; Schmidt, Carsten O; Slutske, Wendy S; Sorice, Rossella; Starr, John M; St Pourcain, Beate; Sutin, Angelina R; Timpson, Nicholas J; Trochet, Holly; Vermeulen, Sita; Vuoksimaa, Eero; Widen, Elisabeth; Wouda, Jasper; Wright, Margaret J; Zgaga, Lina; Porteous, David; Minelli, Alessandra; Palmer, Abraham A; Rujescu, Dan; Ciullo, Marina; Hayward, Caroline; Rudan, Igor; Metspalu, Andres; Kaprio, Jaakko; Deary, Ian J; RΓ€ikkΓΆnen, Katri; Wilson, James F; Keltikangas-JΓ€rvinen, Liisa; Bierut, Laura J; Hettema, John M; Grabe, Hans J; van Duijn, Cornelia M; Evans, David M; Schlessinger, David; Pedersen, Nancy L; Terracciano, Antonio; McGue, Matt; Penninx, Brenda W J H; Martin, Nicholas G; Boomsma, Dorret I
- Year
- 2015
- Journal
- JAMA psychiatry
- PMID
- 25993607
- DOI
- 10.1001/jamapsychiatry.2015.0554
- PMCID
- PMC4667957
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; Pβ=β9.26βΓβ10-9 in the discovery meta-analysis). This association was not replicated (Pβ=β.32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (Pβ=β2.38βΓβ10-8). 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 (1.09βΓβ10-12β<βPβ<β.05) and MDD (4.02βΓβ10-9β<βPβ<β.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.
Region plot for genome-wide significant SNP rs35855737 in the MAGI1 gene on chromosome 3 for neuroticism
Forest plot for genome-wide significant SNP rs35855737 in the MAGI1 gene on chromosome 3 for neuroticism
Manhattan plot for meta-analysis results for neuroticism in 29 discovery cohorts
Quantile-quantile plots for meta-analysis results for neuroticism in 29 discovery cohorts
Results of polygenic risk score analyses predicting MDD and neuroticism based on neuroticism polygenic risk scoresNote: 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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