Dick Danielle M, Edenberg Howard J, Xuei Xiaoling, Goate Alison, Kuperman Sam, Schuckit Marc, Crowe Raymond, Smith Tom L, Porjesz Bernice, Begleiter Henri, Foroud Tatiana
Indiana University School of Medicine, Indianapolis, Indiana, USA.
Alcohol Clin Exp Res. 2004 Jan;28(1):4-9. doi: 10.1097/01.ALC.0000108645.54345.98.
Evidence from human, animal, and in vitro cell models suggests that gamma-aminobutyric acid (GABA), the major inhibitory neurotransmitter in the human central nervous system, is involved in many of the neurochemical pathways that affect alcohol use, abuse, and dependence. Both linkage and association to the region on chromosome 15q that contains a cluster of GABAA receptor genes have previously been reported, but the role of these genes in alcoholism remains inconclusive.
We conducted family-based association analyses by using a large sample of multiplex alcoholic families collected as part of the Collaborative Study on the Genetics of Alcoholism, to test for an association between alcohol dependence and the GABAA receptor genes clustered on chromosome 15q. Multiple single-nucleotide polymorphisms were tested in each of the three chromosome 15q GABAA receptor genes: GABRA5, GABRB3, and GABRG3.
Using both classic trio-based analyses and extended-family analyses, we found consistent evidence of association between alcohol dependence and GABRG3. Nearly all single-nucleotide polymorphisms across the gene yielded evidence of association, and haplotype analyses were highly significant. No consistent evidence of association was observed with either GABRA5 or GABRB3, nor was there evidence for parent-of-origin effects with any of the genes.
These analyses suggest that GABRG3 may be involved in the risk for alcohol dependence. These findings support the theory that the predisposition to alcoholism may be inherited as a general state of central nervous system disinhibition/hyperexcitability that results from an altered responsiveness to GABA.
来自人类、动物及体外细胞模型的证据表明，γ-氨基丁酸（GABA）作为人类中枢神经系统中的主要抑制性神经递质，参与了许多影响酒精使用、滥用及依赖的神经化学通路。此前已有关于15号染色体q区域（该区域包含一组GABAA受体基因）的连锁和关联报道，但这些基因在酒精中毒中的作用仍无定论。
我们利用作为酒精中毒遗传学合作研究一部分收集的大量多基因酒精依赖家庭样本，进行基于家系的关联分析，以检测酒精依赖与15号染色体q区域上成簇的GABAA受体基因之间的关联。对15号染色体上的三个GABAA受体基因（GABRA5、GABRB3和GABRG3）中的每一个基因都检测了多个单核苷酸多态性。
通过经典的基于三联体的分析和扩展家系分析，我们发现了酒精依赖与GABRG3之间存在关联的一致证据。该基因上几乎所有的单核苷酸多态性都产生了关联证据，单倍型分析也具有高度显著性。未观察到GABRA5或GABRB3存在一致的关联证据，也没有证据表明任何一个基因存在亲本来源效应。
这些分析表明，GABRG3可能与酒精依赖风险有关。这些发现支持了这样一种理论，即酒精中毒的易感性可能作为一种中枢神经系统抑制/兴奋过度的一般状态遗传下来，这种状态是由对GABA反应性改变导致的。
