Human Molecular Genetics Advance Access published online on March 4, 2008
Human Molecular Genetics, doi:10.1093/hmg/ddn068
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A regulatory variation in OPRK1, the gene encoding the 
-opioid receptor, is associated with alcohol dependence
1 Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202 2 Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202 3 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202 4 Department of Psychiatry, Washington University School of Medicine, St. Louis, MO 5 Division of Child Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA 6 Department of Psychiatry, University of California, San Diego, CA 7 Department of Genetics, Rutgers University, Piscataway, NJ
* Corresponding author Dr. Howard J. Edenberg Department of Biochemistry and Molecular Biology Indiana University School of Medicine 635 Barnhill Dr, MS4063 Indianapolis, IN 46202-5122 Phone: 317-274-2353 Fax: 317-274-4686 E-mail: edenberg{at}iupui.edu
Received January 28, 2008; Revised February 29, 2008; Accepted February 29, 2008
Variations in OPRK1, which encodes the 
-opioid receptor, are associated with the risk for alcohol dependence. Sequencing DNAs with higher and lower risk haplotypes revealed an insertion/deletion (indel) with a net addition of 830 bp located 1986 bp upstream of the translation start site (1389 bp upstream of the transcription start site). We demonstrated that the upstream region extending from -1647 to -10 bp or from -2312 to -10 bp (relative to the translation start site) could function as a promoter in transient transfection assays. We then determined that the presence of the indel reduced transcriptional activity by half. We used a PCR assay to genotype individuals in 219 multiplex alcohol dependent families of European American descent for the presence or absence of this indel. Family-based association analyses detected significant evidence of association of this insertion with alcoholism; the longer allele (with the indel), which had lower expression, is associated with higher risk for alcoholism. This indel is, therefore, a functional regulatory variation likely to explain at least part of the association of OPRK1 with alcohol dependence.
Current address: Analytical Sciences Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
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