Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent

Abstract

We previously demonstrated that prodynorphin (PDYN) haplotypes and single nucleotide polymorphism (SNP) rs2281285 are associated with alcohol dependence and the propensity to drink in negative emotional states, and recent studies suggest that PDYN gene effects on substance dependence risk may be sex-related. We examined sex-dependent associations of PDYN variation with alcohol dependence and related phenotypes, including negative craving, time until relapse after treatment and the length of sobriety episodes before seeking treatment, in discovery and validation cohorts of European ancestry. We found a significant haplotype-by-sex interaction (p = 0.03), suggesting association with alcohol dependence in males (p = 1E-4) but not females. The rs2281285 G allele increased risk for alcohol dependence in males in the discovery cohort (OR = 1.49, p = 0.002), with a similar trend in the validation cohort (OR = 1.35, p = 0.086). However, rs2281285 showed a trend towards association with increased negative craving in females in both the discovery (beta = 10.16, p = 0.045) and validation samples (OR = 7.11, p = 0.066). In the discovery cohort, rs2281285 was associated with time until relapse after treatment in females (HR = 1.72, p = 0.037); in the validation cohort, it was associated with increased length of sobriety episodes before treatment in males (beta = 13.49, p = 0.001). Our findings suggest that sex-dependent effects of PDYN variants in alcohol dependence are phenotype-specific.

Effect of PDYN rs2281285, rs2235749 and rs910080 gene polymorphisms on the intensity of depression symptoms and negative craving in heroin addicts

“…In the current analysis, although it was not statistically significant (P=0.154), the PDYN rs2281285 AG+GG genotypes (20.19±6.62) had a higher SCS total score than AA genotypes (16.31±8.98), suggesting the association of opiate negative craving with the PDYN rs2281285 variant. This is consistent with previous investigations on alcohol-dependent subjects, which demonstrated an association between the rs2281285 minor G allele and increased negative craving [27][28][29].…”

“…The present study was undertaken with the aim of exploring whether PDYN gene polymorphisms (rs2281285, rs2225749 and rs910080) have an effect on the intensity of depressive symptoms and negative craving in heroin addicts due to the contribution of dynorphin to negative emotional states and to drug-seeking behavior as a result of negative reinforcement. In the literature, the contribution of the PDYN gene to the induction of negative craving [27][28][29] and depression [27] was investigated in only alcohol-dependent subjects. A few studies have examined the effects of PDYN genotypes on susceptibility to opiate addiction in different populations [17][18][19][20][21][22]30].…”

Gender‐specific effects of comorbid depression and anxiety on the propensity to drink in negative emotional states

“…toxicity and/or resetting of allostatic threshold) as well as vulnerability to comorbid mood and anxiety disorders and, especially, SID in male but not female alcoholics. Interestingly, recent analyses of genetic effects on alcoholism‐related phenotypes also indicate the presence of sex‐dependent effects that are also phenotype‐specific: for example, the same genetic variant being associated with alcoholism in males, and with increased propensity to drink in negative emotional situations, negative craving and shorter time for post‐treatment relapse in female but not male alcoholics . Further research is needed to determine which genetic, toxic or other underlying biological and psychosocial mechanisms are responsible for associations between propensity to drink in negative emotional situations and life‐time history of comorbid MDD, SID or AnxD in male and female alcoholics.…”

Genome-wide association mapping of ethanol sensitivity in the Diversity Outbred mouse population

“…Female mice lacking Pdyn showed significantly lower preference and consumption of ethanol, but interestingly, no differences in LORR (Blednov et al 2006). In humans, multiple studies have demonstrated that PDYN haplotypes and individual SNPs (rs2281285) are associated with alcohol dependence and propensity to drink in negative emotional states (Flory et al 2011; Karpyak et al 2013; Winham et al 2015), and that decreased methylation levels of PDYN are associated with craving and alcohol consumption (D’Addario et al 2017).…”