Genetics of Alcoholism

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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
Monozygotic Twins
100 genes 100 home environment
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Understanding Genetic and Environmental
Influences Using Twin Studies
Monozygotic Twins
Dizygotic Twins
100 genes 100 home environment
50 genes 100 home environment
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Understanding Genetic and Environmental
Influences Using Twin Studies
Monozygotic Twins
Dizygotic Twins
100 genes 100 home environment
50 genes 100 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 Underlying GO NO-GO P3
Are Reduced In Alcoholics
DELTA
THETA
P3
Control
Alcoholic
Kamarajan et al., 2003
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Genetic Variants

• There are millions of variants catalogued across
  our genome.
• Many genes have multiple variants
  (polymorphisms).
• These variants risk in different risk for
  substance dependence.

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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
1. Recruit families affected with alcoholism
2. Analyses to identify chromosomal regions
allele-sharing among affecteds within a family
3. Association analyses to identify specific
genes
Gene A
Gene B
Gene C
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Genes Associated with Alcoholism
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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 medicine
• Greater understanding of biologic pathways is
  disorders.
• Understanding of environmental influences
• New targets for personalized medicine