Systematic analysis of Glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior
Systematic analysis of Glutamatergic neurotransmission genes in alcohol dependence and adolescent risky drinking behavior
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DOI：
10.1001/archpsyc.65.7.826
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发表时间：
2008-07-01
影响因子：
--
通讯作者：
Mann, Karl
中科院分区：
文献类型：
--
作者：
Schumann, Gunter;Johann, Monika;Mann, Karl
背景：谷氨酸能神经传递与酒精行为的动物模型有关。目的：研究谷氨酸能神经传递基因的遗传变异是否与人类酒精中毒的遗传基础有关。目的：研究谷氨酸能神经传递基因的遗传变异是否有助于人类酒精中毒的遗传基础。设计：酒精依赖与涵盖10个谷氨酸能基因的单倍型标记单核苷酸多态(SNPs)的关联分析。对这些基因的功能域进行重新测序，发现了204个SNPs。在两个独立的酒精依赖成人患者和对照组以及青少年三人组的两个独立样本中，21个单倍型标记SNP分析可以区分频率为5%或更高的单倍型。地点：德国南部的四个大学医学中心。参与者：1,337名患者和1555名对照组(研究1：544名患者，553名对照；研究2：793名患者，1002名对照)。对144名15岁青少年进行了危险饮酒行为评估。主要观察指标：谷氨酸氨基转移酶、N-甲基-D-天冬氨酸受体亚基NR1NR2ANR2B、mGluR5、nNOS、PRKG2、CAMK4、PI3K调节亚基和CREB的基因型分布与酒精依赖的相关性进行了多因素统计分析。结果：研究1的分析表明，在所选择的基因中，NR2A和mGluR5与人类酒精依赖的相关性最大，优势比分别为2.35和1.69。研究2中的重复分析证实了酒精依赖与NR2A(优势比，2.01)有关，但与mGluR5无关。研究1和研究2的联合分析显示，在Cochran-Mantel-Haenszel测试中有更显著的相关性(P
Context: Glutamatergic neurotransmission is implicated in alcohol-drinking behavior in animal models.Objective: To investigate whether genetic variations in glutamatergic neurotransmission genes, which are known to alter alcohol effects in rodents, contribute to the genetic basis of alcoholism in humans.Design: Association analysis of alcohol dependence and haplotype-tagging single nucleotide polymorphisms (SNPs) covering 10 glutamatergic genes. Resequencing of functional domains of these genes identified 204 SNPs. Haplotypes with a frequency of 5% or greater could be discriminated by 21 haplotype-tagging SNPs analyzed for association in 2 independent samples of alcohol-dependent adult patients and controls as well as adolescent trios.Setting: Four university medical centers in the south of Germany.Participants: One thousand three hundred thirty-seven patients and 1555 controls (study 1: 544 patients, 553 controls; study 2: 793 patients, 1002 controls). One hundred forty-four trios of 15-year-old adolescents assessed for risky drinking behavior.Main Outcome Measures: Genotype profiles for GLAST; N-methyl-D-aspartate-receptor subunits NR1, NR2A, and NR2B; MGLUR5; NNOS; PRKG2; CAMK4; the regulatory subunit of PI3K; and CREB were analyzed for association with alcohol dependence using multivariate statistical analysis. Risky adolescent drinking was tested using the transmission disequilibrium test.Results: Analysis of study 1 revealed that NR2A and MGLUR5 have the greatest relevance for human alcohol dependence among the genes selected with odds ratios of 2.35 and 1.69, respectively. Replication analysis in study 2 confirmed an association of alcohol dependence with NR2A (odds ratio, 2.01) but showed no association with MGLUR5. Combined analysis of study 1 and study 2 exhibited a more significant association on the Cochran-Mantel-Haenszel test (P