Human Molecular Genetics Advance Access originally published online on March 4, 2008
Human Molecular Genetics 2008 17(12):1783-1789; 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 2 Department of Medical and Molecular Genetics and 3 Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN 46202, USA, 4 Department of Psychiatry, Washington University School of Medicine, St Louis, MO, USA, 5 Division of Child Psychiatry, University of Iowa Carver College of Medicine, Iowa City, IA, USA, 6 Department of Psychiatry, University of California, San Diego, CA, USA 7 Department of Genetics, Rutgers University, Piscataway, NJ, USA
* To whom correspondence should be addressed at: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, 635 Barnhill Drive, MS4063 Indianapolis, IN 46202-5122, USA. Tel: +1 3172742353; Fax: +1 3172744686; Email: edenberg{at}iupui.edu
Received January 28, 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.
Present address: Analytical Sciences Research and Development, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.