Associations of prodynorphin sequence variation with alcohol dependence and related traits are phenotype-specific and sex-dependent.
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.
Health Sciences Research, Mayo Clinic, Rochester, MN.
Stacey J
SJ
Winham
Department of Psychiatry, Psychotherapy and Psychosomatics, Martin-Luther-University of Halle-Wittenberg, Halle/Saale, Germany.
Ulrich W
UW
Preuss
Health Sciences Research, Mayo Clinic, Rochester, MN.
Jennifer R
JR
Geske
LMU Munich, Department of Psychiatry, Section Psychiatric Genetics and Neurochemistry, Munich, Germany.
Peter
P
Zill
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN.
John A
JA
Heit
Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
Georgy
G
Bakalkin
Health Sciences Research, Mayo Clinic, Rochester, MN.|Psychiatry and Psychology, Mayo Clinic, Rochester, MN.
Joanna M
JM
Biernacka
Psychiatry and Psychology, Mayo Clinic, Rochester, MN.
Victor M
VM
Karpyak
D000328:Adult; D000437:Alcoholism / Q000235:genetics*; D004745:Enkephalins / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011498:Protein Precursors / Q000235:genetics*; D012737:Sex Factors; D044465:White People / Q000235:genetics
D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin