Genetic and Epigenetic Regulation of Addiction Genes

Ohio State University, Columbus OH

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Abstract

Drug addiction is a complex disorder with a strong genetic component, while the role of epigenetic factors[unreadable] remains unresolved. We propose that the interplay between genetic polymorphisms and epigenetic changes[unreadable] determines gene expression and possibly mRNA processing, serving a critical role in drug addiction. A large[unreadable] portion of suspected addiction susceptibility genes harbors CpG islands, methylation of which represents a[unreadable] main epigenetic mechanism. Both genetic and epigenetic factors likely contribute to addiction susceptibility[unreadable] and physiological changes occurring as a result of substance abuse. We will study these factors in autopsy[unreadable] tissues from the Miami Brain Endowment Bank, containing ~approximately 500 samples from cocaine and other drug[unreadable] abusers and age-matched controls. This repository enables genetic and epigenetic studies in relevant brain[unreadable] regions involved in addiction. CpG methylation can occur randomly between the two allele of a gene[unreadable] (represented in overall expression level), or in an allele-selective fashion. The latter causes an allelic[unreadable] expression imbalance (AEI), which represents a precise and quantitative phenotype for both genetic and[unreadable] epigenetic cis-acting factors. This permits us to address several questions. How does CpG island[unreadable] methylation vary across brain regions, and what is the variability among individuals? Does methylation affect[unreadable] gene expression, alternate promoter usage, or alternative splicing? What is the effect of substance abuse[unreadable] on CpG island methylation in candidate genes, in relevant brain regions? Do epigentic and genetic factors[unreadable] contribute to clinical status (addiction)? In this project, we target genes harboring CpG islands that are[unreadable] implicated in addiction, focusing on biogenic amine pathways, encoding synthetic and catabolic enzymes,[unreadable] vesicular and synaptic reuptake transporters, and receptors (MAOA, MAOB, COMT, TH, DAT, NET, VMAT2,[unreadable] DRD2, CHRNA4). We have developed high-throughput tools for measuring the genetic and epigenetic[unreadable] contribution to mRNA and protein expression, and alternative splicing. Our assays are allele-specific,[unreadable] enabling the evaluation of genetic and epigenetic factors in allelic expression, a powerful tool for assessing[unreadable] the quantitative impact of each factor. This novel approach, applied to anatomically defined brain tissues[unreadable] from drug addicts and controls, has the potential to yield significant insight into the role of and interplay[unreadable] between genetic and epigenetic factors, and add to our understanding of susceptibility to addiction.[unreadable]