Genome wide association for addiction: replicated results and comparisons of two analytic approaches.
Genome wide association for addiction: replicated results and comparisons of two analytic approaches.
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DOI：
10.1371/journal.pone.0008832
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发表时间：
2010-01-21
期刊：
影响因子：
3.7
通讯作者：
Uhl GR
中科院分区：
文献类型：
--
作者：
Drgon T;Zhang PW;Johnson C;Walther D;Hess J;Nino M;Uhl GR
对成瘾物质依赖的脆弱性基本上是可遗传的复杂疾病，其潜在的遗传结构可能是多基因的，许多个体基因的变异有一定的贡献。“非模板”全基因组关联（GWA）方法可以鉴定染色体区域和基因的组，这些染色体区域和基因合在一起更可能含有等位基因变体，这些等位基因变体改变了对物质依赖的脆弱性，而不是偶然的。我们报告了两个独立样本的物质依赖与对照研究志愿者（n = 1620），一个欧洲裔美国人和其他非洲裔美国人使用100万SNP（单核苷酸多态性）的Affyestine基因分型阵列的汇总“非模板”全基因组关联研究。 我们使用两种相关方法评估这两个样本的结果之间的收敛性，这些方法寻求名义上阳性结果的聚类，并使用Monte Carlo和置换方法评估显著性水平。“先收敛后聚类”和“聚类后收敛”分析都记录了从这两个独立数据集获得的结果之间的收敛性，这种收敛性几乎从来没有偶然发现过。以这种方式鉴定的基因也通过个体基因分型的dbGAP数据来鉴定，所述数据比较可卡因依赖个体与对照个体中的等位基因频率。这些重叠的结果鉴定了小的染色体区域，这些区域也被来自其他相关样品的研究的全基因组数据鉴定到比偶然性大得多的程度。这些染色体区域包含的与“细胞粘附”过程相关的基因比预期的要多。它们还含有许多编码抗成瘾药物治疗的潜在靶点的基因。“非模板”GWA方法，寻找染色体区域，其中在多个独立的样品中发现名义上阳性的关联可能是补充经典的，“模板”GWA方法，其中“全基因组”的显着性水平，从单一的情况下与对照比较的SNP数据寻求。
Vulnerabilities to dependence on addictive substances are substantially heritable complex disorders whose underlying genetic architecture is likely to be polygenic, with modest contributions from variants in many individual genes. “Nontemplate” genome wide association (GWA) approaches can identity groups of chromosomal regions and genes that, taken together, are much more likely to contain allelic variants that alter vulnerability to substance dependence than expected by chance. We report pooled “nontemplate” genome-wide association studies of two independent samples of substance dependent vs control research volunteers (n = 1620), one European-American and the other African-American using 1 million SNP (single nucleotide polymorphism) Affymetrix genotyping arrays. We assess convergence between results from these two samples using two related methods that seek clustering of nominally-positive results and assess significance levels with Monte Carlo and permutation approaches. Both “converge then cluster” and “cluster then converge” analyses document convergence between the results obtained from these two independent datasets in ways that are virtually never found by chance. The genes identified in this fashion are also identified by individually-genotyped dbGAP data that compare allele frequencies in cocaine dependent vs control individuals. These overlapping results identify small chromosomal regions that are also identified by genome wide data from studies of other relevant samples to extents much greater than chance. These chromosomal regions contain more genes related to “cell adhesion” processes than expected by chance. They also contain a number of genes that encode potential targets for anti-addiction pharmacotherapeutics. “Nontemplate” GWA approaches that seek chromosomal regions in which nominally-positive associations are found in multiple independent samples are likely to complement classical, “template” GWA approaches in which “genome wide” levels of significance are sought for SNP data from single case vs control comparisons.
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DOI：
10.1073/pnas.0501536102
发表时间：
2005-05-17
影响因子：
11.1
作者：
Hageman, GS;Anderson, DH;Allikmets, R
通讯作者：
Allikmets, R
DOI：
10.1016/s0197-2456(98)00037-3
发表时间：
1998-12-01
期刊：
CONTROLLED CLINICAL TRIALS
影响因子：
--
作者：
Dupont, WD;Plummer, WD
通讯作者：
Plummer, WD
DOI：
10.1002/ajmg.b.30346
发表时间：
2006-12-05
影响因子：
2.8
作者：
Johnson, Catherine;Drgon, Tomas;Uhl, George R.
通讯作者：
Uhl, George R.
影响因子：
11
作者：
Butcher, LM;Meaburn, E;Plomin, R
通讯作者：
Plomin, R
影响因子：
1.8
作者：
Knight, Jo;Saccone, Scott F.;Rice, John P.
通讯作者：
Rice, John P.