A regulatory variation in OPRK1, the gene encoding the κ-opioid receptor, is associated with alcohol dependence

Howard Edenberg, Jun Wang, Huijun Tian, Sirisha Pochareddy, Xiaoling Xuei, Leah Wetherill, Alison Goate, Tony Hinrichs, Samuel Kuperman, John Nurnberger, Marc Schuckit, Jay A. Tischfield, Tatiana Foroud

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Abstract

Variations in OPRK1, which encodes the κ-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.

Original languageEnglish
Pages (from-to)1783-1789
Number of pages7
JournalHuman Molecular Genetics
Volume17
Issue number12
DOIs
StatePublished - Jun 15 2008

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Opioid Receptors
Alcoholism
Genes
Transcription Initiation Site
DNA Sequence Analysis
Haplotypes
Transfection
Alleles
Genotype
Alcohols
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Genetics

Cite this

A regulatory variation in OPRK1, the gene encoding the κ-opioid receptor, is associated with alcohol dependence. / Edenberg, Howard; Wang, Jun; Tian, Huijun; Pochareddy, Sirisha; Xuei, Xiaoling; Wetherill, Leah; Goate, Alison; Hinrichs, Tony; Kuperman, Samuel; Nurnberger, John; Schuckit, Marc; Tischfield, Jay A.; Foroud, Tatiana.

In: Human Molecular Genetics, Vol. 17, No. 12, 15.06.2008, p. 1783-1789.

Research output: Contribution to journalArticle

Edenberg, H, Wang, J, Tian, H, Pochareddy, S, Xuei, X, Wetherill, L, Goate, A, Hinrichs, T, Kuperman, S, Nurnberger, J, Schuckit, M, Tischfield, JA & Foroud, T 2008, 'A regulatory variation in OPRK1, the gene encoding the κ-opioid receptor, is associated with alcohol dependence', Human Molecular Genetics, vol. 17, no. 12, pp. 1783-1789. https://doi.org/10.1093/hmg/ddn068
Edenberg, Howard ; Wang, Jun ; Tian, Huijun ; Pochareddy, Sirisha ; Xuei, Xiaoling ; Wetherill, Leah ; Goate, Alison ; Hinrichs, Tony ; Kuperman, Samuel ; Nurnberger, John ; Schuckit, Marc ; Tischfield, Jay A. ; Foroud, Tatiana. / A regulatory variation in OPRK1, the gene encoding the κ-opioid receptor, is associated with alcohol dependence. In: Human Molecular Genetics. 2008 ; Vol. 17, No. 12. pp. 1783-1789.
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