A regulatory variation in OPRK1, the gene encoding the kappa-opioid receptor, is associated with alcohol dependence.
- Authors
- Edenberg, Howard J; Wang, Jun; Tian, Huijun; Pochareddy, Sirisha; Xuei, Xiaoling; Wetherill, Leah; Goate, Alison; Hinrichs, Tony; Kuperman, Samuel; Nurnberger, John I; Schuckit, Marc; Tischfield, Jay A; Foroud, Tatiana
- Year
- 2008
- Journal
- Human molecular genetics
- PMID
- 18319328
- DOI
- 10.1093/hmg/ddn068
- PMCID
- PMC2405904
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.
5′ region of the OPRK1 gene and fragments used in promoter assays. Boxes 1 and 2 are exons; gray, 5′ untranslated sequence; black, coding sequence. Transcription in direction of top arrow. 1.6 kb is the fragment extending from −1647 to −10 bp relative to the translation start site; 2.3 kb is the fragment with the reference sequence, from −2312 to −10 bp; 3.1 kb is the fragment with the same ends but containing the additional 830 bp of the indel (minor allele).
LLM interpretation
This is a schematic diagram of the 5′ region of the *OPRK1* gene and the specific DNA fragments used for promoter assays. The gene structure is depicted with exons 1 (gray, untranslated) and 2 (black, coding), with an arrow indicating the direction of transcription and a marker for SNP rs35566036. Three promoter fragments are illustrated below the gene map: a 1.6 kb fragment, a 2.3 kb reference fragment, and a 3.1 kb fragment containing an 830 bp indel.
Effect of the indel on promoter function in vitro. Black bars represent the mean expression, gray bars are ±1 standard error. 1.6 kb is the fragment extending from −1647 to −10 bp relative to the translation start site; 2.3 kb is the fragment with the reference sequence, from −2312 to −10 bp; 3.1 kb is the fragment from −2312 to −10 bp but containing the additional 830 bp indel.
LLM interpretation
This bar chart shows the in vitro promoter expression levels for three different genomic fragments: 1.6 kb, 2.3 kb, and 3.1 kb. Expression decreases across the groups, with the 1.6 kb fragment showing the highest expression (approximately 33 units) and the 3.1 kb fragment (containing the indel) showing the lowest (approximately 15 units). Black bars represent the mean expression, while gray bars indicate ±1 standard error.
Genotyping of the indel. PCR was carried out with primers HE3236 and HE3244 as described in the text, followed by electrophoresis on 1% agarose gels. A homozygote lacking the indel is shown as SS, a homozygote with the indel as LL and a heterozygote as SL. M is a 100 bp DNA ladder (New England Biolabs, Ipswitch, MA, USA); the darker bands are 500 and 1000 bp.
LLM interpretation
This image shows an agarose gel electrophoresis result for genotyping an indel. The gel contains a 100 bp DNA ladder (M) and three samples: a homozygote lacking the indel (SS) showing a single lower band, a homozygote with the indel (LL) showing a single higher band, and a heterozygote (SL) showing both bands. The difference in band migration indicates a size difference between the short (S) and long (L) alleles.
Linkage disequilibrium among genotyped markers (r2). At top is a diagram of the gene showing the relative position of the oprk1ins indel (rs35566036) and of the SNPs previously reported (17); associated SNPs are boxed. Below is a diagram of LD between SNPs, calculated as r2.
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