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.
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).
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.
Neuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.
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.
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.
神经质是精神疾病普遍存在的风险因素。它在基因上与重度抑郁症（MDD）重叠，因此是精神遗传学的重要表型。人格遗传学联盟为超过63000名参与者（包括MDD病例）的人格特质全基因组关联分析创建了一个资源库。
通过对基于千人基因组推算的全基因组关联结果进行荟萃分析，确定与神经质相关的基因变异；通过估计基于单核苷酸多态性（SNP）的遗传力，评估SNP所评估的常见基因变异是否能解释神经质的变异；并检查预测神经质的SNP是否也能预测MDD。
设计、设置和参与者：对来自人格遗传学联盟的30个队列进行全基因组关联荟萃分析，这些队列具有全基因组基因型、人格和MDD数据。该研究包括来自29个发现队列的63661名参与者和来自一个复制队列的9786名参与者。参与者来自欧洲、美国或澳大利亚。分析在2012年至2014年期间进行。
通过项目反应理论分析在所有29个发现队列中协调的神经质得分，以及其中2个队列中的临床MDD病例对照状态。
在MAGI1基因的3p14区域发现了一个全基因组显著的SNP（rs35855737；发现荟萃分析中的P = 9.26×10−9）。这种关联未得到重复验证（P = 0.32），但在所有30个队列的荟萃分析中该SNP仍具有全基因组显著性（P = 2.38×10−8）。常见基因变异解释了神经质变异的15%。基于27个队列的神经质荟萃分析得出的多基因得分在另外2个队列中显著预测了神经质（1.09×10−12 < P < 0.05）和MDD（4.02×10−9 < P < 0.05）。
本研究确定了一个新的神经质基因座。该变异位于一个已知基因中，该基因在先前的研究中已与双相情感障碍和精神分裂症相关。此外，该研究表明，神经质受许多小效应的基因变异影响，这些变异要么常见，要么由常见变异标记。这些基因变异也影响MDD。未来的研究应确认MAGI1基因座对神经质的作用，并进一步研究MAGI1与多基因关联与一系列其他与神经质表型相关的精神疾病之间的关联。
