Pooled association genome scanning for alcohol dependence using 104,268 SNPs: Validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism
Pooled association genome scanning for alcohol dependence using 104,268 SNPs: Validation and use to identify alcoholism vulnerability loci in unrelated individuals from the collaborative study on the genetics of alcoholism
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DOI：
10.1002/ajmg.b.30346
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发表时间：
2006-12-05
影响因子：
2.8
通讯作者：
Uhl, George R.
中科院分区：
文献类型：
--
作者：
Johnson, Catherine;Drgon, Tomas;Uhl, George R.
关联基因组扫描可以识别等位基因变异的标记，这些变异导致对复杂疾病的脆弱性，包括酒精依赖。为了提高这种方法的能力和可行性，我们报告了在合并的DNA样本中基于“100 k”微阵列的等位基因频率评估的验证。然后，我们使用这种方法与无关的酒精依赖与控制个人收集的家系酒精中毒遗传学合作研究（COGA）采样。酒精依赖和对照个体之间的等位基因频率差异在合并样本中的104，268个常染色体SNP处以四倍体进行评估。188个SNP提供（1）依赖个体与对照个体之间的最大等位基因频率差异;（2）这些差异的t值>= 3;和（3）聚类，使得51个相对小的染色体区域包含至少三个满足上述标准1和2的SNP（Monte Carlo P = 0.00034）。这些阳性SNP簇提名了感兴趣的基因，其产物涉及细胞信号传导、基因调控、发育、“细胞粘附”和孟德尔疾病。结果收敛与酒精和其他成瘾表型的连锁和关联结果。这些数据支持多基因对酒精依赖脆弱性的贡献。这些SNPs提供了新的工具来帮助理解，预防和治疗酒精滥用和依赖。(c)2006 Wiley-Liss，Inc.
Association genome scanning can identify markers for the allelic variants that contribute to vulnerability to complex disorders, including alcohol dependence. To improve the power and feasibility of this approach, we report validation of "100k" microarray-based allelic frequency assessments in pooled DNA samples. We then use this approach with unrelated alcohol-dependent versus control individuals sampled from pedigrees collected by the Collaborative Study on the Genetics of Alcoholism (COGA). Allele frequency differences between alcohol-dependent and control individuals are assessed in quadruplicate at 104,268 autosomal SNPs in pooled samples. One hundred eighty-eight SNPs provide (1) the largest allele frequency differences between dependent versus control individuals; (2) t values >= 3 for these differences; and (3) clustering, so that 51 relatively small chromosomal regions contain at least three SNPs that satisfy criteria 1 and 2 above (Monte Carlo P = 0.00034). These positive SNP clusters nominate interesting genes whose products are implicated in cellular signaling, gene regulation, development, "cell adhesion," and Mendelian disorders. The results converge with linkage and association results for alcohol and other addictive phenotypes. The data support polygenic contributions to vulnerability to alcohol dependence. These SNPs provide new tools to aid the understanding, prevention, and treatment of alcohol abuse and dependence. (c) 2006 Wiley-Liss, Inc.