Multiple interacting genes and environmental factors determine the risk and trajectory of drug addiction. Expression of genes involved in the risk and consequences of addiction is influenced by environmental factors that in many cases are likely to leave persistent chemical modifications (epigenetic marks) in DNA and chromatin. We propose to comprehensively identify in archived postmortem human brain, changes in gene expression and linked epigenetic marks associated with chronic cocaine dependence. We will study two dopamine-dependent brain regions, the dorsal and ventral striatum. We will profile epigenetic marks in cocaine abusers with both short and long-term drug exposures. For analysis of the transcriptome, we will perform whole genome, strand- specific sequencing of mRNA transcripts (RNA-seq). For the DNA methylome, we will use MeDIP or equivalent technology to map the distribution of methyl CpG's at genome- wide and locus specific levels. The ultimate aim of this proposal is to discover which epigenetic changes in brain accompany the transition from cocaine abuse to chronic cocaine dependence. Discovery of cocaine-associated networks and pathways will provide clues to the etiology of cocaine addiction and will identify likely points of intervention in molecular and biochemical pathways that represent potential therapeutic targets.

Public Health Relevance

Multiple interacting genes and environmental factors underlie the risk of drug addiction. First-time high throughput technologies will be used to develop epigenome maps of human brain, which are essential for understanding how epigenetic mechanisms figure in the neurobiology of drug abuse. We will profile epigenetic marks in human brain from chronic cocaine abusers to better our understanding and treatment of drug addiction.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-GGG-M (50))
Program Officer
Satterlee, John S
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Miami School of Medicine
Schools of Medicine
Coral Gables
United States
Zip Code
Castel, Stephane E; Mohammadi, Pejman; Chung, Wendy K et al. (2016) Rare variant phasing and haplotypic expression from RNA sequencing with phASER. Nat Commun 7:12817
Long, Quan; Argmann, Carmen; Houten, Sander M et al. (2016) Inter-tissue coexpression network analysis reveals DPP4 as an important gene in heart to blood communication. Genome Med 8:15
Turecki, Gustavo; Brent, David A (2016) Suicide and suicidal behaviour. Lancet 387:1227-39
Benitez-Buelga, Carlos; Vaclová, Tereza; Ferreira, Sofia et al. (2016) Molecular insights into the OGG1 gene, a cancer risk modifier in BRCA1 and BRCA2 mutations carriers. Oncotarget 7:25815-25
Hartmann, Katherine; Seweryn, Michał; Handleman, Samuel K et al. (2016) Non-linear interactions between candidate genes of myocardial infarction revealed in mRNA expression profiles. BMC Genomics 17:738
Gross, Jeffrey A; Nagy, Corina; Lin, Li et al. (2016) Global and Site-Specific Changes in 5-Methylcytosine and 5-Hydroxymethylcytosine after Extended Post-mortem Interval. Front Genet 7:120
Hou, Liping; Bergen, Sarah E; Akula, Nirmala et al. (2016) Genome-wide association study of 40,000 individuals identifies two novel loci associated with bipolar disorder. Hum Mol Genet 25:3383-3394
Stacey, Simon N; Kehr, Birte; Gudmundsson, Julius et al. (2016) Insertion of an SVA-E retrotransposon into the CASP8 gene is associated with protection against prostate cancer. Hum Mol Genet 25:1008-18
Cruceanu, Cristiana; Kutsarova, Elena; Chen, Elizabeth S et al. (2016) DNA hypomethylation of Synapsin II CpG islands associates with increased gene expression in bipolar disorder and major depression. BMC Psychiatry 16:286
Turecki, Gustavo; Meaney, Michael J (2016) Effects of the Social Environment and Stress on Glucocorticoid Receptor Gene Methylation: A Systematic Review. Biol Psychiatry 79:87-96

Showing the most recent 10 out of 18 publications