title: Prodynorphin CpG-SNPs associated with alcohol dependence: elevated methylation in the brain of human alcoholics.
abstract: The genetic, epigenetic and environmental factors may influence the risk for neuropsychiatric disease through their effects on gene transcription. Mechanistically, these effects may be integrated through regulation of methylation of CpG dinucleotides overlapping with single-nucleotide polymorphisms (SNPs) associated with a disorder. We addressed this hypothesis by analyzing methylation of prodynorphin (PDYN) CpG-SNPs associated with alcohol dependence, in human alcoholics. Postmortem specimens of the dorsolateral prefrontal cortex (dl-PFC) involved in cognitive control of addictive behavior were obtained from 14 alcohol-dependent and 14 control subjects. Methylation was measured by pyrosequencing after bisulfite treatment of DNA. DNA binding proteins were analyzed by electromobility shift assay. Three PDYN CpG-SNPs associated with alcoholism were found to be differently methylated in the human brain. In the dl-PFC of alcoholics, methylation levels of the C, non-risk variant of 3'-untranslated region (3'-UTR) SNP (rs2235749; C > T) were increased, and positively correlated with dynorphins. A DNA-binding factor that differentially targeted the T, risk allele and methylated and unmethylated C allele of this SNP was identified in the brain. The findings suggest a causal link between alcoholism-associated PDYN 3'-UTR CpG-SNP methylation, activation of PDYN transcription and vulnerability of individuals with the C, non-risk allele(s) to develop alcohol dependence.
authors.affiliation: The Division of Biological Research on Drug Dependence, Department of Pharmaceutical Biosciences, Uppsala University, Uppsala, Sweden.
authors.forename: Malik Mumtaz
authors.initials: MM
authors.lastname: Taqi
authors.forename: Igor
authors.initials: I
authors.lastname: Bazov
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Watanabe
authors.forename: Donna
authors.initials: D
authors.lastname: Sheedy
authors.forename: Clive
authors.initials: C
authors.lastname: Harper
authors.forename: Kanar
authors.initials: K
authors.lastname: Alkass
authors.forename: Henrik
authors.initials: H
authors.lastname: Druid
authors.forename: Parri
authors.initials: P
authors.lastname: Wentzel
authors.forename: Fred
authors.initials: F
authors.lastname: Nyberg
authors.forename: Tatjana
authors.initials: T
authors.lastname: Yakovleva
authors.forename: Georgy
authors.initials: G
authors.lastname: Bakalkin
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000328:Adult; D000368:Aged; D000437:Alcoholism / Q000235:genetics* / Q000473:pathology; D000483:Alleles; D018899:CpG Islands / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics*; D004745:Enkephalins / Q000235:genetics*; D057890:Epigenomics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017397:Prefrontal Cortex / Q000378:metabolism*; D011498:Protein Precursors / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D004745:Enkephalins; D011498:Protein Precursors; C033660:preproenkephalin