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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.

SUBMITTER: Winham SJ

PROVIDER: S-EPMC4621530 | biostudies-literature | 2015 Oct

REPOSITORIES: biostudies-literature

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

Winham Stacey J SJ Preuss Ulrich W UW Geske Jennifer R JR Zill Peter P Heit John A JA Bakalkin Georgy G Biernacka Joanna M JM Karpyak Victor M VM

Scientific reports 20151027

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 sobr ...[more]

PMID: 26502829

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Project description:BackgroundOver 50 years of evidence from research has established that the central dopaminergic reward pathway is likely involved in alcohol dependence (AD). Additional evidence supports a role for dopamine (DA) in other disinhibitory psychopathology, which is often comorbid with AD. Family and twin studies demonstrate that a common genetic component accounts for most of the genetic variance in these traits. Thus, DA-related genes represent putative candidates for the genetic risk that underlies not only AD but also behavioral disinhibition. Many linkage and association studies have examined these relationships with inconsistent results, possibly because of low power, poor marker coverage, and/or an inappropriate correction for multiple testing.MethodsWe conducted an association study on the products encoded by 10 DA-related genes (DRD1-D5, SLC18A2, SLC6A3, DDC, TH, COMT) using a large, ethnically homogeneous sample with severe AD (n = 545) and screened controls (n = 509). We collected genotypes from linkage disequilibrium (LD)-tagging single nucleotide polymorphisms (SNPs) and employed a gene-based method of correction. We tested for association with AD diagnosis in cases and controls and with a variety of alcohol-related traits (including age-at-onset, initial sensitivity, tolerance, maximum daily drinks, and a withdrawal factor score), disinhibitory symptoms, and a disinhibitory factor score in cases only. A total of 135 SNPs were genotyped using the Illumina GoldenGate and Taqman Assays-on-Demand protocols.ResultsOf the 101 SNPs entered into standard analysis, 6 independent SNPs from 5 DA genes were associated with AD or a quantitative alcohol-related trait. Two SNPs across 2 genes were associated with a disinhibitory symptom count, while 1 SNP in DRD5 was positive for association with the general disinhibitory factor score.ConclusionsOur study provides evidence of modest associations between a small number of DA-related genes and AD as well as a range of alcohol-related traits and measures of behavioral disinhibition. While we did conduct gene-based correction for multiple testing, we did not correct for multiple traits because the traits are correlated. However, false-positive findings remain possible, so our results must be interpreted with caution.

Dataset Information

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

Publications

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

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