Novel genes identified in a high-density genome wide association study for nicotine dependence
Novel genes identified in a high-density genome wide association study for nicotine dependence
复制标题
DOI：
10.1093/hmg/ddl441
复制
发表时间：
2007-01-01
影响因子：
3.5
通讯作者：
Ballinger, Dennis G.
中科院分区：
文献类型：
--
作者：
Bierut, Laura Jean;Madden, Pamela A. F.;Ballinger, Dennis G.
烟草使用是世界范围内导致残疾和死亡的主要因素，遗传因素在一定程度上导致了尼古丁依赖的发展。为了确定自然变异有助于尼古丁依赖发展的新基因，我们进行了一项全面的全基因组关联研究，以尼古丁依赖吸烟者为病例，以非依赖吸烟者为对照。为了实现对基因组的高效、快速和成本效益的筛选，这项研究采用了两阶段设计。在第一阶段，在病例池和对照池中完成了超过240万个单核苷酸多态(SNPs)的基因分型。在第二阶段，我们根据汇集的结果中病例和对照之间最显著的等位基因频率差异，选择SNPs进行个体基因分型。用31960个SNPs对1050例病例和879例对照进行了个体基因分型。初步分析发现35个SNPs的P值小于10(-4)(最小P值为1.53×10(-6))。虽然在对多次测试进行校正后，没有一个单独的发现具有统计学意义，但额外的统计分析支持这一组中存在真实的发现。我们的研究提名了几个新的基因，如NRXN1，在尼古丁依赖的发展过程中，同时也确定了一个已知的候选基因，β3烟碱能受体。这项工作预测了大规模全基因组关联研究的未来方向，采用最先进的方法学方法，并与科学界共享数据。
Tobacco use is a leading contributor to disability and death worldwide, and genetic factors contribute in part to the development of nicotine dependence. To identify novel genes for which natural variation contributes to the development of nicotine dependence, we performed a comprehensive genome wide association study using nicotine dependent smokers as cases and non-dependent smokers as controls. To allow the efficient, rapid, and cost effective screen of the genome, the study was carried out using a two-stage design. In the first stage, genotyping of over 2.4 million single nucleotide polymorphisms (SNPs) was completed in case and control pools. In the second stage, we selected SNPs for individual genotyping based on the most significant allele frequency differences between cases and controls from the pooled results. Individual genotyping was performed in 1050 cases and 879 controls using 31 960 selected SNPs. The primary analysis, a logistic regression model with covariates of age, gender, genotype and gender by genotype interaction, identified 35 SNPs with P-values less than 10(-4) (minimum P-value 1.53 x 10(-6)). Although none of the individual findings is statistically significant after correcting for multiple tests, additional statistical analyses support the existence of true findings in this group. Our study nominates several novel genes, such as Neurexin 1 (NRXN1), in the development of nicotine dependence while also identifying a known candidate gene, the beta 3 nicotinic cholinergic receptor. This work anticipates the future directions of large-scale genome wide association studies with state-of-the-art methodological approaches and sharing of data with the scientific community.