title: A regulatory variation in OPRK1, the gene encoding the kappa-opioid receptor, is associated with alcohol dependence.
abstract: Variations in OPRK1, which encodes the kappa-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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. edenberg@iupui.edu
authors.forename: Howard J
authors.initials: HJ
authors.lastname: Edenberg
authors.forename: Jun
authors.initials: J
authors.lastname: Wang
authors.forename: Huijun
authors.initials: H
authors.lastname: Tian
authors.forename: Sirisha
authors.initials: S
authors.lastname: Pochareddy
authors.forename: Xiaoling
authors.initials: X
authors.lastname: Xuei
authors.forename: Leah
authors.initials: L
authors.lastname: Wetherill
authors.forename: Alison
authors.initials: A
authors.lastname: Goate
authors.forename: Tony
authors.initials: T
authors.lastname: Hinrichs
authors.forename: Samuel
authors.initials: S
authors.lastname: Kuperman
authors.forename: John I
authors.initials: JI
authors.lastname: Nurnberger
authors.forename: Marc
authors.initials: M
authors.lastname: Schuckit
authors.forename: Jay A
authors.initials: JA
authors.lastname: Tischfield
authors.forename: Tatiana
authors.initials: T
authors.lastname: Foroud
mesh_terms: D000437:Alcoholism / Q000235:genetics*; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D054643:INDEL Mutation; D017473:Receptors, Opioid, kappa / Q000235:genetics*; D044465:White People
chemical_list: D017473:Receptors, Opioid, kappa