de Moor Marleen H M, van den Berg Stéphanie M, Verweij Karin J H, Krueger Robert F, Luciano Michelle, Arias Vasquez Alejandro, Matteson Lindsay K, Derringer Jaime, Esko Tõnu, Amin Najaf, Gordon Scott D, Hansell Narelle K, Hart Amy B, Seppälä 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 Jüri, 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, Lehtimäki 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-Råback 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, Räikkönen Katri, Wilson James F, Keltikangas-Järvinen 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
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.
Department of Research Methodology, Measurement, and Data Analysis, University of Twente, Enschede, the Netherlands.
JAMA Psychiatry. 2015 Jul;72(7):642-50. doi: 10.1001/jamapsychiatry.2015.0554.
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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