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.
5β² region of the OPRK1 gene and fragments used in promoter assays. Boxes 1 and 2 are exons; gray, 5β² untranslated sequence; black, coding sequence. Transcription in direction of top arrow. 1.6 kb is the fragment extending from β1647 to β10 bp relative to the translation start site; 2.3 kb is the fragment with the reference sequence, from β2312 to β10 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 5β² 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 Β±1 standard error. 1.6 kb is the fragment extending from β1647 to β10 bp relative to the translation start site; 2.3 kb is the fragment with the reference sequence, from β2312 to β10 bp; 3.1 kb is the fragment from β2312 to β10 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 Β±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.
| # | Section | Preview |
|---|---|---|
| 20 | MATERIALS AND METHODS β Statistical analyses | Family-based association analyses were performed using PDT (78) as implemented in the programβ¦ |
| 21 | FUNDING | This national collaborative study is supported by the NIH Grant U10AA008401 from the National⦠|
No entities extracted from this document yet.
No uploaded files.
In this knowledge base
External
| Title | Authors | Journal | Year | Link |
|---|---|---|---|---|
| Kappa-opioid receptor antagonism in the nucleus accumbens shell distinguishes escalated alcohol consumption and negative affective-like behavior from physiological withdrawal in alcohol-dependence. | Lepreux G et al. | β | 2024 | β |
| Insula Dynorphin and Kappa Opioid Receptor Systems Regulate Alcohol Drinking in a Sex-Specific Manner in Mice. | Pina MM et al. | β | 2023 | β |
| The collaborative study on the genetics of alcoholism: Genetics. | Johnson EC et al. | β | 2023 | β |
| An Integrative Transcriptomic Analysis Reveals EGFR Exon-19 E746-A750 Fragment Deletion Regulated miRNA, circRNA, mRNA and lncRNA Networks in Lung Carcinoma. | Chen L et al. | β | 2022 | β |
| Epigenetic and Transcriptional Control of the Opioid Prodynorphine Gene: In-Depth Analysis in the Human Brain. | Nosova O et al. | β | 2021 | β |
| Overview of Genetic Analysis of Human Opioid Receptors. | Spampinato SM | β | 2021 | β |
| Dynorphins in Development and Disease: Implications for Cardiovascular Disease. | Cissom C et al. | β | 2020 | β |
| Epigenetic regulation of the kappa opioid receptor gene by an insertion-deletion in the promoter region. | Lutz PE et al. | β | 2018 | β |
| Genetic association analyses and meta-analysis of Dynorphin-Kappa Opioid system potential functional variants with heroin dependence. | Yuanyuan J et al. | β | 2018 | β |
| Hypermethylation of the ΞΊ1 opioid receptor promoter in Chinese heroin and methamphetamine addicts. | Ji H et al. | β | 2018 | β |
| Maladaptive behavioral regulation in alcohol dependence: Role of kappa-opioid receptors in the bed nucleus of the stria terminalis. | Erikson CM et al. | β | 2018 | β |
| Gene Expression Changes in Glutamate and GABA-A Receptors, Neuropeptides, Ion Channels, and Cholesterol Synthesis in the Periaqueductal Gray Following Binge-Like Alcohol Drinking by Adolescent Alcohol-Preferring (P) Rats. | McClintick JN et al. | β | 2016 | β |
| Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent. | Winham SJ et al. | β | 2015 | β |
| Clinically relevant genetic biomarkers from the brain in alcoholism with representation on high resolution chromosome ideograms. | Manzardo AM et al. | β | 2015 | β |
| Genetics of alcoholism. | Edenberg HJ et al. | β | 2014 | β |
| How to design PET experiments to study neurochemistry: application to alcoholism. | Morris ED et al. | β | 2014 | β |
| LY2456302 is a novel, potent, orally-bioavailable small molecule kappa-selective antagonist with activity in animal models predictive of efficacy in mood and addictive disorders. | Rorick-Kehn LM et al. | β | 2014 | β |
| Neurochemical mechanisms of alcohol withdrawal. | Becker HC et al. | β | 2014 | β |
| Physiology, signaling, and pharmacology of opioid receptors and their ligands in the gastrointestinal tract: current concepts and future perspectives. | Sobczak M et al. | β | 2014 | β |
| The association of genetic polymorphisms in the ΞΊ-opioid receptor 1 gene with body weight, alcohol use, and withdrawal symptoms in patients with methadone maintenance. | Wang SC et al. | β | 2014 | β |
| The one-two punch of alcoholism: role of central amygdala dynorphins/kappa-opioid receptors. | Kissler JL et al. | β | 2014 | β |
| Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states. | Karpyak VM et al. | β | 2013 | β |
| A variant on the kappa opioid receptor gene (OPRK1) is associated with stress response and related drug craving, limbic brain activation and cocaine relapse risk. | Xu K et al. | β | 2013 | β |
| Determination of the in vivo selectivity of a new ΞΊ-opioid receptor antagonist PET tracer 11C-LY2795050 in the rhesus monkey. | Kim SJ et al. | β | 2013 | β |
| NCK2 is significantly associated with opiates addiction in African-origin men. | Liu Z et al. | β | 2013 | β |
| PDYN rs2281285 variant association with drinking to avoid emotional or somatic discomfort. | Preuss UW et al. | β | 2013 | β |
| The endogenous opioid system in human alcoholics: molecular adaptations in brain areas involved in cognitive control of addiction. | Bazov I et al. | β | 2013 | β |
| The ΞΊ-opioid receptor gene as a predictor of response in a cocaine vaccine clinical trial. | Nielsen DA et al. | β | 2013 | β |
| Upregulated dynorphin opioid peptides mediate alcohol-induced learning and memory impairment. | Kuzmin A et al. | β | 2013 | β |
| ΞΊ-Opioid receptors in the central amygdala regulate ethanol actions at presynaptic GABAergic sites. | Kang-Park M et al. | β | 2013 | β |
| Alcohol Dependence and Genes Encoding Ξ±2 and Ξ³1 GABAA Receptor Subunits: Insights from Humans and Mice. | Borghese CM et al. | β | 2012 | β |
| Epistatic effects between variants of kappa-opioid receptor gene and A118G of mu-opioid receptor gene increase susceptibility to addiction in Indian population. | Kumar D et al. | β | 2012 | β |
| Introduction to the special issue "Pharmacotherapies for the treatment of alcohol abuse and dependence" and a summary of patents targeting other neurotransmitter systems. | Bell RL et al. | β | 2012 | β |
| Large scale association analysis for drug addiction: results from SNP to gene. | Guo X et al. | β | 2012 | β |
| Neuropeptide modulation of central amygdala neuroplasticity is a key mediator of alcohol dependence. | Gilpin NW et al. | β | 2012 | β |
| Targeting dynorphin/kappa opioid receptor systems to treat alcohol abuse and dependence. | Walker BM et al. | β | 2012 | β |
| The dynorphin/ΞΊ-opioid receptor system and its role in psychiatric disorders. | Tejeda HA et al. | β | 2012 | β |
| The genetics of the opioid system and specific drug addictions. | Levran O et al. | β | 2012 | β |
| ΞΊ-opioid receptor/dynorphin system: genetic and pharmacotherapeutic implications for addiction. | Butelman ER et al. | β | 2012 | β |
| Fine mapping quantitative trait loci that influence alcohol preference behavior in the High and Low Alcohol Preferring (HAP and LAP) mice. | Bice PJ et al. | β | 2011 | β |
| Candidate genes for alcohol preference identified by expression profiling in alcohol-preferring and -nonpreferring reciprocal congenic rats. | Liang T et al. | β | 2010 | β |
| Genome-wide association study of alcohol dependence implicates a region on chromosome 11. | Edenberg HJ et al. | β | 2010 | β |
| Human and laboratory rodent low response to alcohol: is better consilience possible? | Crabbe JC et al. | β | 2010 | β |
| Pharmacogenetics of alcohol and alcohol dependence treatment. | Kranzler HR et al. | β | 2010 | β |
| Pharmacogenetics of drug dependence: role of gene variations in susceptibility and treatment. | Khokhar JY et al. | β | 2010 | β |
| Search for genetic markers and functional variants involved in the development of opiate and cocaine addiction and treatment. | Yuferov V et al. | β | 2010 | β |
| Dopamine D4 receptor gene exon III polymorphism associated with binge drinking attitudinal phenotype. | Vaughn MG et al. | β | 2009 | β |
| Endogenous opiates and behavior: 2008. | Bodnar RJ | β | 2009 | β |
| Laboratory methods for high-throughput genotyping. | Edenberg HJ et al. | β | 2009 | β |
| Naltrexone aversion and treatment efficacy are greatest in humans and rats that actively consume high levels of alcohol. | Mitchell JM et al. | β | 2009 | β |
| Neuropeptide Y receptor genes are associated with alcohol dependence, alcohol withdrawal phenotypes, and cocaine dependence. | Wetherill L et al. | β | 2008 | β |