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Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence

Item Type:Article
Title:Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence
Creators Name:Hoehe, M.R. and Koepke, K. and Wendel, B. and Rohde, K. and Flachmeier, C. and Kidd, K.K. and Berrettini, W.H. and Church, G.M.
Abstract: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 variants; 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.
Keywords:African Americans, African Continental Ancestry Group, DNA Sequence Analysis, Genetic Polymorphism, Genetic Predisposition to Disease, Haplotypes, Heterozygote, mu Opioid Receptors, Phenotype, Phylogeny, Polymerase Chain Reaction, Substance-Related Disorders, Variation (Genetics)
Source:Human Molecular Genetics
ISSN:0964-6906
Publisher:Oxford University Press (U.K.)
Volume:9
Number:19
Page Range:2895-2908
Date:22 November 2000
Official Publication:http://hmg.oxfordjournals.org/cgi/content/abstract/9/19/2895
PubMed:View item in PubMed

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