Sequence variability and candidate gene analysis in complex disease:: association of μ opioid receptor gene variation with substance dependence
Sequence variability and candidate gene analysis in complex disease:: association of μ opioid receptor gene variation with substance dependence
复制标题
DOI：
10.1093/hmg/9.19.2895
复制
发表时间：
2000-11-22
影响因子：
3.5
通讯作者：
Church, GM
中科院分区：
文献类型：
--
作者：
Hoehe, MR;Köpke, K;Church, GM
为了分析候选基因并建立复杂的基因型-表型关系，我们开发了以下方法：（i）比较多个个体中的候选基因序列信息;（ii）从众多变异体中预测单倍型;和（iii）对单倍型进行分类并鉴定与表型相关的特定序列变体或变体组合（模式），使用人μ阿片受体基因（OPRM 1）作为模型系统，我们结合这些方法来测试OPRM 1在物质中的潜在作用。对250例海洛因/可卡因依赖者和对照者的该主要候选基因的所有已知功能相关区域进行多重序列比较;在172名非洲裔美国人的亚组中鉴定了43种变异，预测了52种不同的单倍型。通过相似性聚类将这些单倍型分为两个功能相关的类别，其中一个在物质依赖个体中显著更频繁，这一类别的共同点是与物质依赖相关的序列变异特征模式[-1793T-->A，-1699Tins，-1320A-->G，-111C-->T，+17C-->T（A6 V）]。这项研究提供了一个例子的方法，已成功地应用于建立复杂的基因型-表型关系的存在下，丰富的DNA序列变异。
To analyze candidate genes and establish complex genotype-phenotype relationships against a background of high natural genome sequence variability, we have developed approaches to (i) compare candidate gene sequence information in multiple individuals; (ii)predict haplotypes from numerous varian ts; and (iii) classify haplotypes and identify specific sequence variants, or combinations of variants (pattern), associated with the phenotype, Using the human mu opioid receptor gene (OPRM1) as a model system, we have combined these approaches to test a potential role of OPRM1 in substance (heroin/cocaine) dependence, All known functionally relevant regions of this prime candidate gene were analyzed by multiplex sequence comparison in 250 cases and controls; 43 variants were identified and 52 different haplotypes predicted in the subgroup of 172 African-Americans. These haplotypes were classified by similarity clustering into two functionally related categories, one of which was significantly more frequent in substance-dependent individuals, Common to this category was a characteristic pattern of sequence variants [-1793T-->A, -1699Tins, -1320A-->G, -111C-->T, +17C-->T (A6V)], which was associated with substance dependence. This study provides an example of approaches; that have been successfully applied to the establishment of complex genotype-phenotype relationships in the presence of abundant DNA sequence variation.