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.

Allele-specific DNA methylation reinforces PEAR1 enhancer activity

“…Association studies between CpG-SNPs and certain phenotypes are increasing, [23][24][25][26][27][28][29] but the molecular characterization of their mechanism of action still remains a challenge. Most of the CpG-SNPs functionally characterized are located in the 59-untranslated region or promoter regions, [48][49][50][51] while PEAR1 rs12041331 is located in a noncoding intronic region, yet with specific enhancer features.…”

“…DNA methylation has been extensively described in the control of cell specification, cancer, and other human diseases 21 and cooperates with histone modifications in rendering the chromatin more or less accessible for transcription factors, thereby influencing gene expression. 22 Despite reported associations of CpG-SNPs with multiple diseases, [23][24][25][26][27][28][29] the role of CpG-SNPs in regulating platelet phenotypes was never investigated.…”

A Functional 3′UTR Polymorphism (rs2235749) of Prodynorphin Alters microRNA-365 Binding in Ventral Striatonigral Neurons to Influence Novelty Seeking and Positive Reward Traits

“…The SN/VSM neurons are, however, more specifically characterized by the predominant expression of the opioid neuropeptide prodynorphin (PDYN) (Heiman et al, 2008). Individual differences within the 3′ untranslated region (3′UTR) of the PDYN gene have been shown to be associated with the abuse of various drugs, specifically cocaine, alcohol, and heroin (Clarke et al, 2009;Yuferov et al, 2009;Taqi et al, 2011). However, no study has yet addressed whether such differences in PDYN are associated with behavioral endophenotypes relevant to psychiatric disorders and risk-taking behaviors and no information exists regarding the association with cannabis dependence, a drug which is now widely used by teens and young adults.…”

Epigenetics in the Human Brain

“…Still, hundreds of promoters are subject to epigenetic changes that seemingly continue into old age, and these data, taken together, leave little doubt that chromatin structures undergo remodeling throughout the lifespan of the human brain (Hernandez et al, 2011;Numata et al, 2012;Siegmund et al, 2007), including neurons and other terminally differentiated cells (Cheung et al, 2010). Based on postmortem brain work, epigenetic risk architectures are beginning to emerge for a number of common psychiatric conditions and disorders, including autism (Shulha et al, 2011), schizophrenia (Akbarian, 2010), depression and bipolar disorder (Gamazon et al, 2012;Tang et al, 2011) and alcoholism (Taqi et al, 2011) Table 1). We predict that only very few, if any, loci will show group-based differences when assayed in genome-wide epigenetic screens.…”