Sequence variability and candidate gene analysis in complex disease: association of mu opioid receptor gene variation with substance dependence.
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.
Hoehe
M R
MR
Genome Research, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany. mhoehe@mdc-berlin.de
Köpke
K
K
Wendel
B
B
Rohde
K
K
Flachmeier
C
C
Kidd
K K
KK
Berrettini
W H
WH
Church
G M
GM
D000328:Adult; D001741:Black or African American; D044383:Black People / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics*; D006239:Haplotypes / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D010641:Phenotype; D010802:Phylogeny; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic / Q000235:genetics; D017450:Receptors, Opioid, mu / Q000235:genetics*; D017422:Sequence Analysis, DNA; D019966:Substance-Related Disorders / Q000235:genetics*
D017450:Receptors, Opioid, mu