A regulatory variation in OPRK1, the gene encoding the kappa-opioid receptor, is associated with alcohol dependence.
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.
Edenberg
Howard J
HJ
Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA. edenberg@iupui.edu
Wang
Jun
J
Tian
Huijun
H
Pochareddy
Sirisha
S
Xuei
Xiaoling
X
Wetherill
Leah
L
Goate
Alison
A
Hinrichs
Tony
T
Kuperman
Samuel
S
Nurnberger
John I
JI
Schuckit
Marc
M
Tischfield
Jay A
JA
Foroud
Tatiana
T
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
D017473:Receptors, Opioid, kappa