Lappalainen Jaakko, Krupitsky Evgeny, Kranzler Henry R, Luo Xingguang, Remizov Mikhail, Pchelina Sofia, Taraskina Anastaisa, Zvartau Edwin, Räsanen Pirkko, Makikyro Taru, Somberg Lucia K, Krystal John H, Stein Murray B, Gelernter Joel
Department of Psychiatry, Yale University School of Medicine, New Haven, Connecticut, USA.
Am J Med Genet B Neuropsychiatr Genet. 2007 Mar 5;144B(2):183-92. doi: 10.1002/ajmg.b.30377.
Synaptic actions of gamma-amino butyric acid (GABA) have been implicated in many facets of ethanol's effects and risk for alcoholism. We examined whether variation in glutamate decarboxylase-2 (GAD2), a gene encoding for a major enzyme in the synthesis of GABA, contributes to risk of alcohol dependence (AD). We screened GAD2 for sequence variants using dHPLC in a population of 96 individuals. Several single nucleotide polymorphisms (SNPs), including four rare non-synonymous polymorphisms, were identified. Thirteen SNPs located in the GAD2 gene were genotyped in a sample of 113 Russian males with AD and 100 Russian male controls. These analyses revealed a modest association between the functional GAD2 -243 A > G SNP (rs2236418) and AD (allele P = 0.038, genotype P = 0.008). An additional sample of 138 Russian males with AD were genotyped for the GAD2 -243 A > G. These analyses supported an association of this polymorphism with AD (combined sample allele P = 0.038, genotype P = 0.0009). We extended these findings to additional populations: a sample of 538 college students assessed using the AUDIT and a sample of European-American (EA) AD subjects (n = 235) and controls (n = 310). Analyses in these populations did not support a role for GAD2 in alcoholism. In summary, the results of an extensive search for an association of GAD2 with AD suggest that variation in GAD2 is not a major risk factor for AD in EAs. The functional promoter GAD2 -243 A > G variant may influence risk for AD in some populations, or its role may be limited to susceptibility to severe AD.
γ-氨基丁酸（GABA）的突触作用与乙醇作用的多个方面以及酒精中毒风险有关。我们研究了谷氨酸脱羧酶-2（GAD2）（一种编码GABA合成中主要酶的基因）的变异是否会导致酒精依赖（AD）风险。我们使用变性高效液相色谱（dHPLC）在96名个体中筛选了GAD2的序列变异。鉴定出了几个单核苷酸多态性（SNP），包括四个罕见的非同义多态性。在113名患有AD的俄罗斯男性和100名俄罗斯男性对照样本中对位于GAD2基因中的13个SNP进行了基因分型。这些分析揭示了功能性GAD2 -243 A>G SNP（rs2236418）与AD之间存在适度关联（等位基因P = 0.038，基因型P = 0.008）。对另外138名患有AD的俄罗斯男性样本进行了GAD2 -243 A>G基因分型。这些分析支持了这种多态性与AD的关联（合并样本等位基因P = 0.038，基因型P = 0.0009）。我们将这些发现扩展到其他人群：使用酒精使用障碍识别测试（AUDIT）评估的538名大学生样本以及欧美（EA）AD受试者（n = 235）和对照（n = 310）样本。这些人群中的分析不支持GAD2在酒精中毒中的作用。总之，对GAD2与AD关联进行广泛搜索的结果表明，GAD2的变异不是EA人群中AD的主要危险因素。功能性启动子GAD2 -243 A>G变异可能在某些人群中影响AD风险，或者其作用可能仅限于对严重AD的易感性。
