genetics of alcoholism laura jean bierut, md washington university
TRANSCRIPT
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Genetics of Alcoholism
Laura Jean Bierut, MD
Washington University
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A Part of Medicine
As with many illnesses in medicine, alcoholism is a complex disorder.
Clusters in families. Genetic contribution. Changing environment influences the
risk.
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Alcohol Dependence Clusters in Families
Children of alcoholics are at 2- to 4-fold higher risk for developing alcohol problems.
About 50% of brothers and 25% sisters of an alcoholic are also alcoholic.
Yet, most individuals in a family are not affected with alcoholism.
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Evidence for Genetic Factors
Adoptees and biologic relatives
Twins - Monozygotic and Dizygotic
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Adoption Studies
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Adoption Studies
Adoptive Parents Biologic Parents
Adopted Child
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Understanding Genetic and Environmental Influences Using Twin Studies
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Understanding Genetic and Environmental Influences Using Twin Studies
100% genes100% home environment
Monozygotic Twins
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Understanding Genetic and Environmental Influences Using Twin Studies
100% genes100% home environment
Monozygotic Twins Dizygotic Twins
50% genes100% home environment
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Understanding Genetic and Environmental Influences Using Twin Studies
100% genes100% home environment
Monozygotic Twins Dizygotic Twins
50% genes100% home environment
We are a combination of our genes and environment.
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Alcohol Dependence - A many step process
Initiation
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Alcohol Dependence - A many step process
Initiation
Regular alcohol use
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Alcohol Dependence - A many step process
Initiation
Regular alcohol use
Alcohol Dependence
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Common and Specific Factors
• Some risk factors may increase the risk of alcoholism and related disorders – such as conduct disorder and drug dependence.
• Other risk factors may act specifically as a risk factor for alcoholism.
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Theta + Delta Oscillations UnderlyingGO NO-GO P3 Are Reduced In Alcoholics
THETA DELTA
Kamarajan et al., 2003
Alcoholic
Control
P3
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There are millions of variants catalogued across our genome. Many genes have
multiple variants (polymorphisms). These variants risk in
different risk for substance dependence.
Genetic Variants
Eye Color Gene Eye Color Gene (blue)(blue)
Eye Color Gene Eye Color Gene (brown)(brown)
Tongue RollerTongue RollerGeneGene
(roller)(roller)
Tongue RollerTongue RollerGeneGene
(non-roller)(non-roller)
Hair Color GeneHair Color Gene(dark)(dark)
Hair Color GeneHair Color Gene(blonde)(blonde)
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Approaches to Genetic Studies
Candidate gene examination -
Family based or case control approach
Hypothesis driven
Whole genome approach
Generally case control approach
Hypothesis free
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COGACollaborative Study of the Genetics of Alcoholism
“The long-term objective of this multi-dimensional interdisciplinary research project is to characterize the genetic factors involved in the determination of predisposition to alcoholism. This substantial undertaking involves the expertise of biochemists, clinicians, geneticists, neuropsychologists, neurophysiologists, and statisticians.”
--original COGA grant application, 1989
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Genetic Strategy
0
0.5
1
1.5
2
2.5
0 10 20 30 40 50 60 70 80 90 100110120130140150160cM
Lod Scores
Wave 1
Wave 2
Combined
1. Recruit families affected with alcoholism
2. Analyses to identify chromosomal regions
3. Association analyses to identify specific genes
allele-sharing among affecteds within a family
Gene A Gene B Gene C
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Genes Associated with Alcoholism
ALDH Aldehyde metabolism
ADH4 Alcohol metabolism
GABRA2
And many others
Gaba receptor
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Association strategy
Multiple analytic methods
Multiple genetic variants in each gene
Examination across the region
Consistency of results
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Genes Associated with Alcoholism
Multiple genes are associated with alcoholism.
Several independent studies replicated findings.
We now have genes that influence the risk for the development of alcoholism.
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Cessation- The Final Step
Initiation
Regular Alcohol Use
Alcohol Dependence
Cessation
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Treatment of addiction today, even the best evidence-based treatment,
often comes down to a trial and error process.
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Genetics is here to stay
Genetic findings open valuable possibilities for the future of medicineGreater understanding of biologic
pathways is disorders.Understanding of environmental influencesNew targets for personalized medicine