Human Molecular Genetics, 2000, Vol. 9, No. 19 2895-2908
© 2000 Oxford University Press
Sequence variability and candidate gene analysis in complex disease: association of µ opioid receptor gene variation with substance dependence
1Genome Research, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, 2GenProfile AG, Robert-Rössle-Strasse 10, D-13125 Berlin, Germany, 3Department of Genetics, Yale University School of Medicine, New Haven, CT 06520, USA, 4Center for Neurobiology and Behavior, University of Pennsylvania, Philadelphia, PA 19104, USA and 5Department of Genetics, Harvard Medical School, Boston, MA 02115, USA
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 µ 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, –1320AG, –111CT, +17CT (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.
+ To whom correspondence should be addressed at: Genome Research, Max-Delbrück-Center for Molecular Medicine, Robert-Rössle-Strasse 10, D-13092 Berlin, Germany. Tel: +49 30 9489 2167; Fax: +49 30 9489 2166; Email: mhoehe@mdc-berlin.de
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