Genetics and Substance Abuse

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Genetics and Substance Abuse
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Genetics is the Study of Heritable Phenomena

• Concordance rate of relatives for disease
• Monozygotic vs. dizygotic twins
• Increased risk in 1st degree relatives over
  general population
• Adoption studies separate genetic vs
  environmental factors in families
• Adopted away concordance genetic
• Not adopted concordance environmental
• Heritability of substance abuse d/os 50

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Substance Abuse as Pharmacogenetic Phenotype(?)

• Differential response to xenobiotic
• aversion
• reinforcement
• Complex genetic trait by definition
• no d/o without exposure
• May be relatively tractable genetic problem
• drugs are potent selective agents
• exposures are well-defined

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Helpful Dichotomy 1

• Mendelian versus complex trait genetics
• Mendelian
• Single major gene
• High penetrance (probability of mutation -gt
  disease)
• Complex
• Multiple gene effects
• Non-genetic component
• Low penetrance

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Mendelian Influences on Substance Abuse I

• Aldehyde dehydrogenase
• Intermediate step in ethanol metabolism
• High prevalence of inactive genetic variant -
  8-45 in Asian populations
• Acetaldehyde is toxic (disulfiram)
• Protective factor for alcohol abuse

alcohol dehydrogenase
aldehyde dehydrogenase
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Mendelian Influences on Substance Abuse II

• Brunner Syndrome - Dutch kindred
• Borderline MR
• Aggressive behavior
• Severe alcoholism
• X linked
• Mapped on X chromosome to region including MAOs
• Fibroblast cultures had no MAOA activity
• Non-sense mutation in monoamine oxidase A gene
• Mutation is very rare

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Helpful Dichotomy 2

• Candidate Gene Approach
• Screen Gene Based on Hypothesis or Model
• Mapping Approach
• Screen Genetic Markers Throughout Genome
• Identify Linked or Associated Markers
• Identify Mutations in Genes in region
• Both rely on linkage!
• In most cases

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Haplotype Approach to DRD2 Association with
Heroin Dependence
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Two Questions/One Answer

• What is the exception to the requirement of
  linkage for association studies?
• What is the most statistically powerful strategy
  for genotyping association samples?

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Dopamine Metabolism
Dopamine Metabolism
MAO
DAT

TH
AADC
tyrosine
Dopamine
VMAT
L-DOPA
DBH
Norepinephrine
Receptor
Receptor
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Plasma DBH is Under genetic Control
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Plasma DBHActivity is Tightly Associated with
-1021C-gtT