Variations in GABRA2, encoding the α2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations
Variations in GABRA2, encoding the α2 subunit of the GABAA receptor, are associated with alcohol dependence and with brain oscillations
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DOI：
10.1086/383283
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发表时间：
2004-04-01
影响因子：
9.8
通讯作者：
Begleiter, H
中科院分区：
文献类型：
--
作者：
Edenberg, HJ;Dick, DM;Begleiter, H
酒精中毒是一种具有遗传和环境双重危险因素的复杂疾病。为了确定影响酗酒风险的基因，我们系统地确定并仔细评估了家庭中有多个酗酒者的个体。连锁和关联分析表明，染色体4p的一个区域包含影响定量内表型、β频率范围（13 - 28赫兹）的脑振荡和酗酒风险的基因。为了确定影响这些表型的单个基因，我们对位于连接区域中心的四个GABA(a)受体基因GABRG1、GABRA2、GABRA4和GABRB1内的69个单核苷酸多态性（snp）进行了连锁不平衡分析。GABA(A)受体介导酒精的重要作用，也调节β频率。GABRA2中有31个snp与酒精中毒有显著关联，但在其侧面基因的20个snp中只有1个。25个GABRA2 snp，但只有一个在侧面基因的snp，与β频率的大脑振荡有关。与酒精依赖关系最强的区域从内含子3延伸到GABRA2的3'端；GABRA2区域的43个连续三snp单倍型均高度显著。三snp单倍型与酒精中毒相关，P = 0.000022。在高风险和低风险单倍型之间没有发现编码差异，表明这种影响是通过基因调控介导的。GABRA2与酒精依赖和脑电图的β频率密切相关，结合该基因在两种表型中的作用的生物学证据，表明GABRA2可能通过调节神经兴奋水平影响对酒精依赖的易感性。
Alcoholism is a complex disease with both genetic and environmental risk factors. To identify genes that affect the risk for alcoholism, we systematically ascertained and carefully assessed individuals in families with multiple alcoholics. Linkage and association analyses suggested that a region of chromosome 4p contained genes affecting a quantitative endophenotype, brain oscillations in the beta frequency range (13 - 28 Hz), and the risk for alcoholism. To identify the individual genes that affect these phenotypes, we performed linkage disequilibrium analyses of 69 single-nucleotide polymorphism (SNPs) within a cluster of four GABA(A) receptor genes, GABRG1, GABRA2, GABRA4, and GABRB1, at the center of the linked region. GABA(A) receptors mediate important effects of alcohol and also modulate beta frequencies. Thirty-one SNPs in GABRA2, but only 1 of the 20 SNPs in the flanking genes, showed significant association with alcoholism. Twenty-five of the GABRA2 SNPs, but only one of the SNPs in the flanking genes, were associated with the brain oscillations in the beta frequency. The region of strongest association with alcohol dependence extended from intron 3 past the 3' end of GABRA2; all 43 of the consecutive three-SNP haplotypes in this region of GABRA2 were highly significant. A three-SNP haplotype was associated with alcoholism, with P = .00000022. No coding differences were found between the high-risk and low-risk haplotypes, suggesting that the effect is mediated through gene regulation. The very strong association of GABRA2 with both alcohol dependence and the beta frequency of the electroencephalogram, combined with biological evidence for a role of this gene in both phenotypes, suggest that GABRA2 might influence susceptibility to alcohol dependence by modulating the level of neural excitation.