Clarimon Jordi, Gray Rebecca R, Williams Lindsey N, Enoch Mary-Anne, Robin Robert W, Albaugh Bernard, Singleton Andrew, Goldman David, Mulligan Connie J
Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
Alcohol Clin Exp Res. 2007 Apr;31(4):546-54. doi: 10.1111/j.1530-0277.2007.00338.x.
Alpha-synuclein is involved in dopaminergic neurotransmission and has been implicated in a number of neurodegenerative disorders, such as Parkinson's disease. Recent studies, in humans and in rat and monkey models, have suggested that alpha-synuclein may play a role in the development and maintenance of certain addictive disorders.
Fifteen single-nucleotide polymorphisms (SNPs) in the alpha-synuclein gene (SNCA) and 1 upstream microsatellite repeat (NACP-REP1) were assayed in Southwest (SW; n=514) and Plains (n=420) American Indian populations. Patterns of linkage disequilibrium (LD) at SNCA were determined for the 2 populations and compared with Caucasian, African, and Asian populations in the HapMap database (http://www.hapmap.org). Assayed alleles and constructed haplotypes in the study populations were tested for association with 4 clinical phenotypes [alcohol dependence, alcohol use disorders, drug dependence, and drug use disorders (lifetime diagnoses)] as well as with 2 symptom count phenotypes (all 18 questions and the 8 questions diagnostic for alcohol dependence).
Patterns of LD at SNCA were similar in both Indian populations and were consistent with the LD structure in other populations as reflected in the HapMap database. Single allele tests revealed significant associations between 4 SNPs and drug dependence in the SW population and between 2 of those SNPs plus 2 other SNPs and drug dependence in SW males only. In the Plains population, a significant association was detected only in males between 2 SNPs and alcohol use disorders and between 1 SNP and alcohol dependence. In the SW population, 1 SNP was marginally significant with the total symptom count. However, in all cases, the support was modest and disappeared with correction for multiple comparisons. No association was found between constructed haplotypes and any of the phenotypes in either population.
Despite modest support for association between multiple SNCA SNPs and several of the addictive disorders tested in this study, statistical significance disappeared after correction for multiple testing. Thus, our data do not support a role for a variant in the SNCA gene that contributes to alcohol or drug addiction in the 2 studied American Indian populations. Future research may focus on variants in the promoter region that could cause the changes in mRNA and protein levels observed in previous studies.
α-突触核蛋白参与多巴胺能神经传递，并与多种神经退行性疾病有关，如帕金森病。最近在人类以及大鼠和猴子模型中的研究表明，α-突触核蛋白可能在某些成瘾性疾病的发生和维持中起作用。
在西南（SW；n = 514）和平原（n = 420）美洲印第安人群体中检测了α-突触核蛋白基因（SNCA）中的15个单核苷酸多态性（SNP）和1个上游微卫星重复序列（NACP-REP1）。确定了这两个群体中SNCA的连锁不平衡（LD）模式，并与HapMap数据库（http://www.hapmap.org）中的高加索、非洲和亚洲人群进行比较。对研究群体中检测到的等位基因和构建的单倍型进行测试，以确定其与4种临床表型[酒精依赖、酒精使用障碍、药物依赖和药物使用障碍（终生诊断）]以及2种症状计数表型（所有18个问题以及用于酒精依赖诊断的8个问题）之间的关联。
两个印第安人群体中SNCA的LD模式相似，并且与HapMap数据库中反映的其他群体的LD结构一致。单等位基因测试显示，4个SNP与SW群体中的药物依赖之间存在显著关联，其中2个SNP加上另外2个SNP仅与SW男性中的药物依赖之间存在显著关联。在平原群体中，仅在男性中检测到2个SNP与酒精使用障碍之间以及1个SNP与酒精依赖之间存在显著关联。在SW群体中，1个SNP与总症状计数之间存在边缘显著性。然而，在所有情况下，支持力度都不大，并且在进行多重比较校正后消失。在两个群体中，构建的单倍型与任何表型之间均未发现关联。
尽管本研究中多个SNCA SNP与所测试的几种成瘾性疾病之间的关联得到了一定程度的支持，但在进行多重检验校正后，统计学显著性消失。因此，我们的数据不支持SNCA基因中的变异在这两个研究的美洲印第安人群体中导致酒精或药物成瘾的作用。未来的研究可能集中在启动子区域的变异上，这些变异可能导致先前研究中观察到的mRNA和蛋白质水平的变化。
