Genetics & Addiction Jonathan D. Pollock, Ph.D.  Division of Neuroscience & Behavioral Research  National Institute on Dru...
NIDA’S GENETICS PROGRAM <ul><li>Extramural Program: </li></ul><ul><ul><li>Genetic Epidemiology </li></ul></ul><ul><ul><ul>...
Addiction is a Heritable Disorder <ul><li>Evidence : </li></ul><ul><ul><li>Twin Studies </li></ul></ul><ul><ul><li>Adoptio...
Addiction is a Heritable Disorder:  Twin Studies
<ul><li>Genetic Basis to Preference for Drugs of Abuse </li></ul><ul><ul><li>Example:  Morphine preference mapped: </li></...
<ul><li>Possible designs: </li></ul><ul><ul><li>heritability estimates  </li></ul></ul><ul><ul><li>genome wide scans </li>...
<ul><li>Genes are part of addiction vulnerability:  </li></ul><ul><ul><li>Initiation (limited genetic influence?) </li></u...
<ul><li>Variants of genes associated with drug abuse: </li></ul><ul><ul><li>FAAH missense mutation is associated with drug...
Genes Affecting Drug metabolism <ul><li>Ethanol     Acetaldehyde     Acetate </li></ul><ul><ul><li>- Individuals with de...
SNP Genome Wide Association Scan and Polydrug Abuse
<ul><li>NIDA Genetics Consortium –established1999 </li></ul><ul><ul><li>17 researchers from 11 different institutions  </l...
The NIDA Center for Genetic Studies <ul><li>The NIDA Center for Genetic Studies   </li></ul><ul><ul><li>Data/biosample rep...
Molecular phenotyping: genes patterns <ul><li>Every human cell has approximately 30,000 genes, some turned on and some tur...
NORMAL CONTROL COCAINE WITHDRAWAL Walker, Feinberg & Self, 2000, unpublished Gene Expression by Microarray Profiling Low l...
<ul><ul><li>DAT/SERT Knockout </li></ul></ul><ul><ul><ul><li>Conditioned place preference to cocaine is blocked </li></ul>...
<ul><li>Tolerance: </li></ul><ul><ul><li>Beta-Arrestin </li></ul></ul><ul><ul><ul><li>Details </li></ul></ul></ul><ul><li>...
Why do Genes Matter <ul><li>Better understanding of environmental factors in addiction </li></ul><ul><li>Will improve trea...
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  1. 1. Genetics & Addiction Jonathan D. Pollock, Ph.D. Division of Neuroscience & Behavioral Research National Institute on Drug Abuse National Institutes of Health Department of Health And Human Services
  2. 2. NIDA’S GENETICS PROGRAM <ul><li>Extramural Program: </li></ul><ul><ul><li>Genetic Epidemiology </li></ul></ul><ul><ul><ul><ul><li>Twin Studies </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Adoption studies </li></ul></ul></ul></ul><ul><ul><li>Molecular Genetic Studies </li></ul></ul><ul><ul><li>Model Genetic Organisms </li></ul></ul><ul><ul><ul><ul><li>Mice </li></ul></ul></ul></ul><ul><ul><ul><ul><li>C. elegans </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Zebra fish </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Drosophila </li></ul></ul></ul></ul><ul><li>Intramural Research Program (NIDA-IRP) </li></ul>
  3. 3. Addiction is a Heritable Disorder <ul><li>Evidence : </li></ul><ul><ul><li>Twin Studies </li></ul></ul><ul><ul><li>Adoption Studies </li></ul></ul><ul><ul><li>Inbred Rodent Strains </li></ul></ul>
  4. 4. Addiction is a Heritable Disorder: Twin Studies
  5. 5. <ul><li>Genetic Basis to Preference for Drugs of Abuse </li></ul><ul><ul><li>Example: Morphine preference mapped: </li></ul></ul><ul><ul><li>Chromosome 1, 6, 10 in mice </li></ul></ul><ul><ul><ul><ul><li>Linkage on chromosome 10 maps to mu opioid receptor </li></ul></ul></ul></ul>Addiction is a Heritable Disorder: Inbred Strains of Rodents
  6. 6. <ul><li>Possible designs: </li></ul><ul><ul><li>heritability estimates </li></ul></ul><ul><ul><li>genome wide scans </li></ul></ul><ul><ul><li>candidate gene studies </li></ul></ul><ul><li>Types of studies: </li></ul><ul><ul><li>sib pairs </li></ul></ul><ul><ul><li>family studies </li></ul></ul><ul><ul><li>association studies </li></ul></ul>Research Designs for Human Genetic Studies
  7. 7. <ul><li>Genes are part of addiction vulnerability: </li></ul><ul><ul><li>Initiation (limited genetic influence?) </li></ul></ul><ul><ul><li>Dependence </li></ul></ul><ul><ul><li>Withdrawal </li></ul></ul><ul><ul><li>Medical Consequences </li></ul></ul><ul><li>Some specific genes have been implicated in addiction </li></ul>Genes Implicated in Addiction Candidate Genes
  8. 8. <ul><li>Variants of genes associated with drug abuse: </li></ul><ul><ul><li>FAAH missense mutation is associated with drug dependence </li></ul></ul><ul><ul><li>Dopamine beta-hydroxylase (D BH) – cocaine-induced paranoia </li></ul></ul><ul><ul><li>Polymorphism in promoter region of prodynorphin gene may be </li></ul></ul><ul><ul><li>associated with protection against cocaine dependence </li></ul></ul><ul><ul><li>Gene variants in nicotinic alpha 7 promoter associated with </li></ul></ul><ul><ul><li>decreased expression of nicotinic alpha 7 subunit message </li></ul></ul><ul><ul><li>in different regions of schizophrenic brains and with sensory </li></ul></ul><ul><ul><li>gating defects in schizophrenics </li></ul></ul><ul><ul><li>5HT1B receptor variant is associated with conduct disorder and </li></ul></ul><ul><li> Alcoholism </li></ul>Genes Implicated in Addiction
  9. 9. Genes Affecting Drug metabolism <ul><li>Ethanol  Acetaldehyde  Acetate </li></ul><ul><ul><li>- Individuals with defects in this metabolism pathway have a 5-10-fold reduction in risk for alcoholism </li></ul></ul><ul><li>Nicotine  Cotinine </li></ul><ul><ul><li>- Individuals with defects in this metabolism pathway appear to smoke fewer cigarettes </li></ul></ul>ADH2 ADH3 ALDH2 ALDH3 CYP2A6
  10. 10. SNP Genome Wide Association Scan and Polydrug Abuse
  11. 11. <ul><li>NIDA Genetics Consortium –established1999 </li></ul><ul><ul><li>17 researchers from 11 different institutions </li></ul></ul><ul><li>Studies focusing on addiction to: </li></ul><ul><ul><li>Opiates </li></ul></ul><ul><ul><li>Cocaine </li></ul></ul><ul><ul><li>Nicotine </li></ul></ul><ul><ul><li>Poly drug abuse </li></ul></ul>Extramural Program: Human Molecular Genetics
  12. 12. The NIDA Center for Genetic Studies <ul><li>The NIDA Center for Genetic Studies </li></ul><ul><ul><li>Data/biosample repository </li></ul></ul><ul><ul><li>The repository uses the blood samples to generate </li></ul></ul><ul><ul><li>immortalized cell lines, as a permanent source of DNA </li></ul></ul><ul><ul><li>The anonymized data are stored in a central Database </li></ul></ul><ul><ul><li>Has the advantage of pooling data increase power and </li></ul></ul><ul><ul><li>facilitate sharing </li></ul></ul>
  13. 13. Molecular phenotyping: genes patterns <ul><li>Every human cell has approximately 30,000 genes, some turned on and some turned off I the addicted state </li></ul><ul><li>Microarray technology can simultaneously analyze activity of thousands of genes, and thereby provide an overall pattern of gene expression for dug addiction </li></ul>
  14. 14. NORMAL CONTROL COCAINE WITHDRAWAL Walker, Feinberg & Self, 2000, unpublished Gene Expression by Microarray Profiling Low level High level
  15. 15. <ul><ul><li>DAT/SERT Knockout </li></ul></ul><ul><ul><ul><li>Conditioned place preference to cocaine is blocked </li></ul></ul></ul><ul><ul><li>mGluR 5-receptor Knockout </li></ul></ul><ul><ul><ul><li>Mice do not self administer cocaine </li></ul></ul></ul><ul><ul><li>Muscarinic M5 receptor deletion </li></ul></ul><ul><ul><ul><li>Mice show no preference for opioids </li></ul></ul></ul><ul><ul><li>Alpha 1b adrenergic receptor knockout </li></ul></ul><ul><ul><ul><li>Oral self-administration of cocaine and morphine decreased </li></ul></ul></ul><ul><ul><li>Substance P receptor knockout </li></ul></ul><ul><ul><ul><li>Rewarding effects of opiates but not cocaine are absent </li></ul></ul></ul><ul><ul><li>Cannabinoid CB1 receptor knockout </li></ul></ul><ul><ul><ul><li>Self-administer cocaine but not morphine </li></ul></ul></ul>Mouse Knockouts: Finding Drug Targets for Treatment ofDrug Abuse
  16. 16. <ul><li>Tolerance: </li></ul><ul><ul><li>Beta-Arrestin </li></ul></ul><ul><ul><ul><li>Details </li></ul></ul></ul><ul><li>Withdrawal </li></ul><ul><ul><li>CREB </li></ul></ul><ul><ul><ul><li>Details </li></ul></ul></ul><ul><li>Addiction </li></ul><ul><ul><li>Delta-fosB </li></ul></ul><ul><ul><ul><li>Details </li></ul></ul></ul>Genetic Organisms are Uncovering Mechanisms of Action of Drugs of Abuse
  17. 17. Why do Genes Matter <ul><li>Better understanding of environmental factors in addiction </li></ul><ul><li>Will improve treatment interventions </li></ul><ul><li>Facilitate understanding the neurobiology of addiction and drug abuse </li></ul>
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