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

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
3R01DA022199-02S1
Application #
7418493
Study Section
Special Emphasis Panel (ZDA1-RXL-E (07))
Program Officer
Caulder, Mark
Project Start
2006-09-27
Project End
2011-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
2
Fiscal Year
2007
Total Cost
$7,640
Indirect Cost
Name
Ohio State University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
832127323
City
Columbus
State
OH
Country
United States
Zip Code
43210
Sullivan, D; Pinsonneault, J K; Papp, A C et al. (2013) Dopamine transporter DAT and receptor DRD2 variants affect risk of lethal cocaine abuse: a gene-gene-environment interaction. Transl Psychiatry 3:e222
Sadee, W; Wang, D; Papp, A C et al. (2011) Pharmacogenomics of the RNA world: structural RNA polymorphisms in drug therapy. Clin Pharmacol Ther 89:355-65
Moyer, Robert A; Wang, Danxin; Papp, Audrey C et al. (2011) Intronic polymorphisms affecting alternative splicing of human dopamine D2 receptor are associated with cocaine abuse. Neuropsychopharmacology 36:753-62
Pinsonneault, Julia K; Han, Dawn D; Burdick, Katherine E et al. (2011) Dopamine transporter gene variant affecting expression in human brain is associated with bipolar disorder. Neuropsychopharmacology 36:1644-55
Smith, Ryan M; Alachkar, Houda; Papp, Audrey C et al. (2011) Nicotinic ?5 receptor subunit mRNA expression is associated with distant 5' upstream polymorphisms. Eur J Hum Genet 19:76-83
Bertolino, Alessandro; Taurisano, Paolo; Pisciotta, Nicola Marco et al. (2010) Genetically determined measures of striatal D2 signaling predict prefrontal activity during working memory performance. PLoS One 5:e9348
Blasi, Giuseppe; Lo Bianco, Luciana; Taurisano, Paolo et al. (2009) Functional variation of the dopamine D2 receptor gene is associated with emotional control as well as brain activity and connectivity during emotion processing in humans. J Neurosci 29:14812-9
Bertolino, Alessandro; Fazio, Leonardo; Caforio, Grazia et al. (2009) Functional variants of the dopamine receptor D2 gene modulate prefronto-striatal phenotypes in schizophrenia. Brain 132:417-25
Bertolino, Alessandro; Fazio, Leonardo; Di Giorgio, Annabella et al. (2009) Genetically determined interaction between the dopamine transporter and the D2 receptor on prefronto-striatal activity and volume in humans. J Neurosci 29:1224-34
Roe, Brian E; Tilley, Michael R; Gu, Howard H et al. (2009) Financial and psychological risk attitudes associated with two single nucleotide polymorphisms in the nicotine receptor (CHRNA4) gene. PLoS One 4:e6704

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