Drgon Tomas, D'Addario Claudio, Uhl George R
Molecular Neurobiology Branch, NIH Intramural Research Program, NIDA, DHHS, Baltimore, Maryland 21224, USA.
Am J Med Genet B Neuropsychiatr Genet. 2006 Dec 5;141B(8):854-60. doi: 10.1002/ajmg.b.30349.
Strong genetic contributions to individual differences in vulnerability to addictions are well supported by classical genetic studies. Linkage and association genome scans for addiction vulnerability have provided converging evidence for several chromosomal regions which are likely to harbor allelic variants that contribute to such vulnerability. We and others have delineated a candidate addiction-associated chromosome 4p12 "rSA3" region based on convergent data from association genome scanning studies in polysubstance abusers [Uhl et al. (2001); Am J Hum Genet 69(6):1290-1300], linkage-based studies in alcoholism [Long et al. (1998); Am J Med Genet 81(3):216-221; Reich et al. (1998); Am J Med Genet 81(3):207-215] and association-based studies for alcoholism and association-based studies for individual differences in electroencephalographic (EEG) spectral power phenotypes [Porjesz et al. (2002); Proc Natl Acad Sci USA 99(6):3729-3733; Edenberg et al. (2004); Am J Hum Genet 74(4):705-714]. The rSA3 region contains interesting candidate genes that encode the alpha 2, alpha 4, beta 1, and gamma 1 receptor subunits for the principal brain inhibitory neurotransmitter, gamma-aminobutyric acid (GABA) [Covault et al. (2004); Am J Med Genet Part B 129B:104-109; Edenberg et al. (2004); Am J Hum Genet 74(4):705-714; Lappalainen et al. (2005); Alcohol Clin Exp Res 29(4):493-498]. We now report assessment of single nucleotide polymorphism (SNP) genotypes in this region in three samples of substance abusers and controls. These results delineate the haplotypes and patterns of linkage disequilibrium in this region, focus attention of the GABRA2 gene and identify modest associations between GABRA2 genotypes and addiction phenotypes. These results are consistent with modest roles for GABRA2 variants in addiction vulnerabilities.
经典遗传学研究充分支持了基因对成瘾易感性个体差异的强大影响。针对成瘾易感性的连锁和关联基因组扫描为几个染色体区域提供了趋同证据，这些区域可能含有导致这种易感性的等位基因变体。基于多物质滥用者关联基因组扫描研究的趋同数据 [Uhl等人（2001年）；《美国人类遗传学杂志》69(6):1290 - 1300]、酒精中毒的连锁研究 [Long等人（1998年）；《美国医学遗传学杂志》81(3):216 - 221；Reich等人（1998年）；《美国医学遗传学杂志》81(3):207 - 215] 以及酒精中毒的关联研究和脑电图（EEG）频谱功率表型个体差异的关联研究 [Porjesz等人（2002年）；《美国国家科学院院刊》99(6):3729 - 3733；Edenberg等人（2004年）；《美国人类遗传学杂志》74(4):705 - 714]，我们和其他人已经划定了一个与成瘾相关的候选4号染色体p12 “rSA3” 区域。rSA3区域包含有趣的候选基因，这些基因编码主要脑抑制性神经递质γ-氨基丁酸（GABA）的α2、α4、β1和γ1受体亚基 [Covault等人（2004年）；《美国医学遗传学杂志》B辑129B:104 - 109；Edenberg等人（2004年）；《美国人类遗传学杂志》74(4):705 - 714；Lappalainen等人（2005年）；《酒精临床与实验研究》29(4):493 - 498]。我们现在报告对三组物质滥用者和对照组样本中该区域单核苷酸多态性（SNP）基因型的评估。这些结果描绘了该区域的单倍型和连锁不平衡模式，将注意力集中在GABRA2基因上，并确定了GABRA2基因型与成瘾表型之间的适度关联。这些结果与GABRA2变体在成瘾易感性中的适度作用一致。
