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

Hum Mol Genet. 2000 Nov 22;9(19):2895-908. doi: 10.1093/hmg/9.19.2895.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Black People / genetics
  • Black or African American
  • Genetic Predisposition to Disease / genetics*
  • Genetic Variation / genetics*
  • Haplotypes / genetics*
  • Heterozygote
  • Humans
  • Phenotype
  • Phylogeny
  • Polymerase Chain Reaction
  • Polymorphism, Genetic / genetics
  • Receptors, Opioid, mu / genetics*
  • Sequence Analysis, DNA
  • Substance-Related Disorders / genetics*


  • Receptors, Opioid, mu