Association of the κ-opioid system with alcohol dependence

Xuei, Xiaoling; Dick, Danielle M.; Flury-Wetherill, Leah; Tian, Huijun; Agrawal, Arpana; Bierut, Laura J.; Goate, Alison M.; Bucholz, Kathleen K.; Schuckit, Marc A.; Nürnberger, John I.; Tischfield, Jay A.; Kuperman, Samuel; Porjesz, Bernice; Begleiter, Henri; Foroud, Tatiana; Edenberg, Howard J.

doi:10.1038/sj.mp.4001882

Cited by 166 publications

(145 citation statements)

References 65 publications

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“…In contrast to the study of OPRD1 by Mayer et al, 40 we did not observe an association between the synonymous variant C921T and OD (though a specific haplotype harboring its C-allele was associated with AD, CD, and especially with OD); instead, a significant association between the nonsynonymous variant G80T (or Cys27Phe) and OD was observed. Moreover, our results are consistent with the findings from a recent study by Xuei et al 48 that OPRK1 variants are associated with risk for AD. They found that five SNP variants in OPRK1 intron 2 were associated with AD.…”

Section: Discussionsupporting

confidence: 93%

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

et al. 2007

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Eleven single-nucleotide polymorphisms (SNPs) spanning OPRD1 were examined in 1063 European Americans (EAs) (620 cases with substance dependence (SD), including 557 with alcohol dependence (AD), 225 with cocaine dependence (CD) and 111 with opioid dependence (OD), and 443 controls). Nominally significant associations (P < 0.05) of five SNPs with SD were observed; only the association of the non-synonymous variant G80T with OD remained significant after correction for multiple testing using SNPSpD. Haplotype analyses with six tag SNPs indicated that a specific haplotype GCAACT, which harbors G80T G-allele and C921T C-allele, was significantly associated with AD (v 2 = 14.82, degrees of freedom (d.f.) = 1, P < 0.001), CD (v 2 = 9.19, d.f. = 1, P = 0.002) and OD (v 2 = 20.68, d.f. = 1, P < 0.001). Logistic regression analyses, with sex and age being considered, demonstrated that this haplotype had a risk effect on AD (P = 0.03, b = 1.86, odds ratio (OR) = 6.43) and especially on OD (P < 0.001, b = 3.92, OR = 50.57). Moreover, seven SNPs covering OPRK1 were examined in the majority of the above subjects (390 cases, including 327 AD, 177 CD and 97 OD subjects, and 358 controls). Although no significant differences in allele, genotype or haplotype frequency distributions were seen between cases and controls, a specific OPRK1 haplotype, GGCTTCT, was significantly associated with AD (v 2 = 8.12, d.f. = 1, P = 0.004). Logistic regression analyses also revealed its risk effect on AD (P = 0.009, b = 1.06, OR = 2.90). Population stratification artifact was not observed in the sample. Taken together, our findings supported a positive association between OPRD1 variants and SD, and a positive haplotypic association between OPRK1 and AD in EAs.

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Section: Discussionsupporting

confidence: 93%

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

et al. 2007

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“…As novelty seeking and reward learning are important risk conferring factors with respect to neuropsychiatric disorders, especially addiction, we focused on two SNPs (rs2235749, rs910080) implicated in substance use disorders (Xuei et al, 2006;Yuferov et al, 2009). All genotypes conformed to Hardy-Weinberg equilibrium.…”

Section: ′Utr Polymorphisms Of the Pdyn Gene Are Associated With Behmentioning

confidence: 99%

“…PDYN SNPs rs2235749 and rs910080 (assay IDs 2507439 and 2507541, respectively) were chosen based on published data that specifically implicated the 3′UTR SNPs in substance dependence (Xuei et al, 2006;Yuferov et al, 2009). Linkage disequilibrium (LD) analysis was also carried out for SNPs in the PDYN gene +/ − 10 kb using the 1000 Genomes data based on racially mixed reference populations and with a minor allele frequency of at least 0.05.…”

Section: Genotypingmentioning

confidence: 99%

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

Egervári

Jutras‐Aswad

Landry

et al. 2016

Neuropsychopharmacol

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Genetic factors impact behavioral traits relevant to numerous psychiatric disorders and risk-taking behaviors, and different lines of evidence have indicated that discrete neurobiological systems contribute to such individual differences. In this study, we explored the relationship of genetic variants of the prodynorphin (PDYN) gene, which is enriched in the striatonigral/striatomesencephalic pathway, a key neuronal circuit implicated in positive 'Go' behavioral choice and action. Our multidisciplinary approach revealed that the single nucleotide polymorphism (SNP) rs2235749 (in high linkage disequilibrium with rs910080) modifies striatal PDYN expression via impaired binding of miR-365, a microRNA that targets the PDYN 3′-untranslated region (3′UTR), and is significantly associated to novelty-and reward-related behavioral traits in humans and translational animal models. Carriers of the rs2235749G allele exhibited increased levels of PDYN 3′UTR in vitro and had elevated mRNA expression in the medial nucleus accumbens shell (NAcSh) and caudate nucleus in postmortem human brains. There was an association of rs2235749 with novelty-seeking trait and a strong genotype-dose association with positive reinforcement behavior in control subjects, which differed in cannabis-dependent individuals. Using lentiviral miRZip-365 constructs selectively expressed in Pdyn-neurons of the NAcSh, we demonstrated that the Pdyn-miR365 interaction in the NAcSh directly influences novelty-seeking exploratory behavior and facilitates self-administration of natural reward. Overall, this translational study suggests that genetically determined miR-365-mediated epigenetic regulation of PDYN expression in mesolimbic striatonigral/striatomesencephalic circuits possibly contributes to novelty seeking and positive reinforcement traits.

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“…Recent studies of humans of European-American descent demonstrate that variations in the genes encoding KOR and dynorphin, OPRK1 and PDYN, are associated with alcohol dependence (Xuei et al, 2006;Edenberg et al, 2008;Karpyak et al, 2012). In addition, animal studies using rats show that activation of KORs with a selective KOR agonist reduces voluntary ethanol intake (Lindholm et al, 2001), whereas a selective KOR antagonist increases alcohol self-administration (Mitchell et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

κ-Opioid Receptors in the Central Amygdala Regulate Ethanol Actions at Presynaptic GABAergic Sites

Kang-Park

Kieffer

Roberts

et al. 2013

J Pharmacol Exp Ther

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Association of the κ-opioid system with alcohol dependence

Cited by 166 publications

References 65 publications

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

The OPRD1 and OPRK1 loci in alcohol or drug dependence: OPRD1 variation modulates substance dependence risk

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

κ-Opioid Receptors in the Central Amygdala Regulate Ethanol Actions at Presynaptic GABAergic Sites

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