全基因组关联分析随后进行的重复研究表明了一个与神经质相关的新候选基因。

Genomewide association analysis followed by a replication study implicates a novel candidate gene for neuroticism.

作者信息

van den Oord Edwin J C G, Kuo Po-Hsiu, Hartmann Annette M, Webb B Todd, Möller Hans-Jürgen, Hettema John M, Giegling Ina, Bukszár József, Rujescu Dan

机构信息

Center for Biomarker Research and Personalized Medicine, Medical College of Virginia, Virginia Commonwealth University, PO Box 980533, Richmond, VA 23298-0533, USA.

出版信息

Arch Gen Psychiatry. 2008 Sep;65(9):1062-71. doi: 10.1001/archpsyc.65.9.1062.

DOI:10.1001/archpsyc.65.9.1062

PMID:18762592

Abstract

CONTEXT

Neuroticism is a trait that reflects a tendency toward negative mood states. It has long been linked to internalizing psychiatric conditions, such as anxiety and depression, and it accounts for much of the substantial comorbidity seen between these disorders.

OBJECTIVE

To identify common genetic variants that affect neuroticism to better understand (the comorbidity between) a broad range of psychiatric disorders and to develop effective treatments.

DESIGN, SETTING, AND PARTICIPANTS: More than 420,000 genetic markers were tested for their association with neuroticism in a genomewide association study (GWAS). The GWAS sample consisted of 1227 healthy individuals ascertained from a US national sampling frame and available from the National Institute of Mental Health genetics repository. The most promising markers were subsequently tested in a German replication sample comprising 1880 healthy individuals.

MAIN OUTCOME MEASURES

A strict definition of replication (same marker, same direction of effects, and same measure) combined with a threshold we proposed previously for declaring significance in genetic studies that ensures a mean probability of producing false-positive findings of less than 10%.

RESULTS

The most promising results in the GWAS and replication samples were single-nucleotide polymorphisms (SNPs) in the gene MAMDC1. These SNPs all tagged the same 2 haplotypes and had P values of 10(-5) to 10(-6) in the GWAS sample and of .006 to .02 in the replication sample. Furthermore, the replication involved the same SNPs and the same direction of effects. In a combined analysis of all data, several SNPs were significant according to the threshold that allows for 10% false-positive findings.

CONCLUSIONS

The small effect sizes may limit the prognostic, diagnostic, and therapeutic use of SNP markers such as those in MAMDC1. However, the present study demonstrates the potential of a GWAS to discover potentially important pathogenic pathways for which clinically more powerful (bio)markers may eventually be developed.

摘要

背景

神经质是一种反映负面情绪状态倾向的特质。长期以来，它一直与内化性精神疾病相关，如焦虑症和抑郁症，并且它在这些疾病之间大量的共病现象中占很大比例。

目的

识别影响神经质的常见基因变异，以更好地理解广泛的精神疾病之间的（共病情况）并开发有效的治疗方法。

设计、设置和参与者：在一项全基因组关联研究（GWAS）中，对超过42万个基因标记与神经质的关联进行了测试。GWAS样本由从美国全国抽样框架中确定的1227名健康个体组成，可从美国国立精神卫生研究所基因库获得。随后，在一个由1880名健康个体组成的德国重复样本中对最有前景的标记进行了测试。

主要观察指标

严格的重复定义（相同的标记、相同的效应方向和相同的测量方法），结合我们先前为基因研究中宣布显著性而提出的阈值，该阈值确保产生假阳性结果的平均概率小于10%。

结果

GWAS和重复样本中最有前景的结果是基因MAMDC1中的单核苷酸多态性（SNP）。这些SNP都标记了相同的2个单倍型，在GWAS样本中的P值为10^(-5)至10^(-6)，在重复样本中的P值为0.006至0.02。此外，重复涉及相同的SNP和相同的效应方向。在对所有数据的综合分析中，根据允许10%假阳性结果的阈值，几个SNP具有显著性。