Allelic and haplotypic association of GABRA2 with alcohol dependence
Allelic and haplotypic association of GABRA2 with alcohol dependence
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DOI：
10.1002/ajmg.b.30091
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发表时间：
2004-08-15
影响因子：
2.8
通讯作者：
Kranzler, HR
中科院分区：
文献类型：
--
作者：
Covault, J;Gelernter, J;Kranzler, HR
酒精依赖是一种高度流行的疾病，与严重的发病率和死亡率有关。由于GABA（A）神经递质受体是酒精的几种行为效应的重要介质，编码GABA相关蛋白的基因是影响酒精依赖风险的功能候选者。两次全基因组扫描显示酒精依赖与染色体4p上的一个区域有关，该区域包含一组编码GABA（A）受体亚基的基因。最近对该区域进行精细定位的努力表明，酒精依赖与编码GABA（A）受体α-2亚基（GABRA 2）的基因存在单倍型关联。我们检查了10个单核苷酸多态性（SNPs）跨越该基因的编码区的样本中的欧洲裔美国人酒精依赖（n = 446），对照组（n = 334）筛选排除物质使用障碍。有证据表明，跨越GABRA 2基因中部和3 '部分的98，000个唇的7个相邻标记物与酒精依赖相关（P值范围= 0.008-0.03）。当检查排除诊断为可卡因或阿片类药物依赖或重度抑郁发作的酒精依赖受试者子集（n = 198）时，这7个SNP之间的关联强度增加（P值范围= 0.002-0.007）。两种常见的单倍型在该地区占90.8%的染色体。在对照组中，55.6%的染色体存在更常见的单倍型，而酒精依赖受试者为48.2%（P = 0.007），酒精依赖但无共病药物依赖或抑郁症的受试者为45.8%（P = 0.003）。这些发现重复并扩展了最近报道的发现，这些发现共同强调了GABRA 2基因座多态性变异对酒精依赖风险的潜在贡献。(C)2004 Wiley-Liss，Inc.
Alcohol dependence is a highly prevalent disorder that is associated with serious morbidity and mortality. Because the GABA(A) neurotransmitter receptor is an important mediator for several behavioral effects of alcohol, genes encoding GABA-related proteins are functional candidates to influence risk of alcohol dependence. Two genome-wide scans showed linkage of alcohol dependence to a region on chromosome 4p, which contains a cluster of genes encoding GABA(A) receptor subunits. A recent effort to fine map that region showed a haplotypic association of alcohol dependence to the gene encoding the GABA(A) receptor alpha-2 subunit (GABRA2). We examined 10 single nucleotide polymorphisms (SNPs) spanning the coding region of this gene in samples of European American subjects with alcohol dependence (n = 446), and controls (n = 334) screened to exclude substance use disorders. There was evidence of association to alcohol dependence for seven adjacent markers spanning 98,000 lip in the middle and 3'-portion of the GABRA2 gene (range of P-values = 0.008-0.03). When the subset of the alcohol-dependent subjects excluding those with a diagnosis of cocaine or opioid dependence or major depressive episode (n = 198) was examined, the strength of the association was increased across these 7 SNPs (range of P-values = 0.002-0.007). Two common haplotypes in this region accounted for 90.8% of chromosomes. The more common haplotype was present in 55.6% of control group chromosomes versus 48.2% of alcohol-dependent subjects (P = 0.007) and 45.8% of subjects with alcohol dependence but no co-morbid drug dependence or depression (P = 0.003). These findings replicate and extend recently reported findings, which together underscore the potential contribution of polymorphic variation at the GABRA2 locus to the risk for alcohol dependence. (C) 2004 Wiley-Liss, Inc.