Association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states

Abstract

Synthetic kappa-opioid receptor (KOR) agonists induce dysphoric and pro-depressive effects, and variations in the KOR (OPRK1) and prodynorphin (PDYN) genes have been shown to be associated with alcohol dependence. We genotyped 23 single nucleotide polymorphisms (SNPs) in the PDYN and OPRK1 genes in 816 alcohol dependent subjects and investigated their association with (1) negative craving measured by a subscale of the Inventory of Drug Taking Situations (IDTS); (2), a self-reported history of depression; and, (3) the intensity of depressive symptoms measured by the Beck Depression Inventory-II (BDI). In addition, 13 of the 23 PDYN and OPRK1 SNPs, which were previously genotyped in a set of 1248 controls, were used to evaluate association with alcohol dependence. SNP and haplotype tests of association were performed. Analysis of a haplotype spanning the PDYN gene (rs6045784, rs910080, rs2235751, rs2281285) revealed significant association with alcohol dependence (p=0.00079) and with negative craving (p=0.0499). A candidate haplotype containing the PDYN rs2281285-rs1997794 SNPs that was previously associated with alcohol dependence was also associated with negative craving (p=0.024) and alcohol dependence (p=0.0008) in this study. A trend for association between depression severity and PDYN variation was detected. No associations of OPRK1 gene variation with alcohol dependence or other studied phenotypes were found. These findings support the hypothesis that sequence variation in the PDYN gene contributes to both alcohol dependence and the induction of negative craving in alcohol dependent subjects.

Impaired periamygdaloid-cortex prodynorphin is characteristic of opiate addiction and depression

“…While much of the published data have been obtained from experimental animal studies (15,16,35), recent clinical investigations have also demonstrated that variants of the PDYN gene relate to transcriptional alterations of PDYN mRNA expression and are associated with depressive traits and negative craving in alcoholics (36,37). The current study adds to the field by directly examining the human brain to provide neuropathophysiological insights that have not been previously reported.…”

Genetic studies of alcohol dependence in the context of the addiction cycle

“…A recent paper reported an association of the PDYN gene with alcohol dependence and the propensity to drink in negative emotional states. Further an association of a PDYN variant with drinking to avoid emotional or somatic discomfort was also reported (Karpyak et al, 2013; Preuss et al, 2013). …”

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

“…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).…”