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Genetics of Alcoholism. Laura Jean Bierut, MD Washington University. 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. Alcohol Dependence Clusters in Families.

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Genetics of alcoholism

Genetics of Alcoholism

Laura Jean Bierut, MD

Washington University


A part of medicine
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.


Alcohol dependence clusters in families
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.


Evidence for genetic factors
Evidence for Genetic Factors

  • Adoptees and biologic relatives

  • Twins - Monozygotic and Dizygotic



Adoption studies1
Adoption Studies

Adoptive Parents

Biologic Parents

Adopted Child



Understanding genetic and environmental influences using twin studies1
Understanding Genetic and Environmental Influences Using Twin Studies

Monozygotic Twins

100% genes

100% home environment


Understanding genetic and environmental influences using twin studies2
Understanding Genetic and Environmental Influences Using Twin Studies

Monozygotic Twins

Dizygotic Twins

100% genes

100% home environment

50% genes

100% home environment


Understanding genetic and environmental influences using twin studies3
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.


Alcohol dependence a many step process
Alcohol Dependence - Twin StudiesA many step process

Initiation


Alcohol dependence a many step process1
Alcohol Dependence - Twin StudiesA many step process

Initiation

Regular alcohol use


Alcohol dependence a many step process2
Alcohol Dependence - Twin StudiesA many step process

Initiation

Regular alcohol use

Alcohol Dependence


Common and specific factors
Common and Specific Factors Twin Studies

  • 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.


Theta + Delta Oscillations Underlying Twin Studies

GO NO-GO P3 Are Reduced In Alcoholics

DELTA

THETA

P3

Control

Alcoholic

Kamarajan et al., 2003


Eye Color Gene (brown) Twin Studies

Eye Color Gene (blue)

Hair Color Gene(dark)

Hair Color Gene(blonde)

Tongue RollerGene(non-roller)

Tongue RollerGene(roller)

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.


Approaches to genetic studies
Approaches to Genetic Studies Twin Studies

  • Candidate gene examination -

    Family based or case control approach

    Hypothesis driven

  • Whole genome approach

    Generally case control approach

    Hypothesis free


Coga collaborative study of the genetics of alcoholism
COGA Twin StudiesCollaborative 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


Genetic strategy
Genetic Strategy Twin Studies

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



Association strategy
Association strategy Twin Studies

  • Multiple analytic methods

  • Multiple genetic variants in each gene

  • Examination across the region

  • Consistency of results


Genes associated with alcoholism1
Genes Associated with Alcoholism Twin Studies

  • Multiple genes are associated with alcoholism.

  • Several independent studies replicated findings.

  • We now have genes that influence the risk for the development of alcoholism.


Cessation the final step
Cessation- Twin StudiesThe Final Step

Initiation

Regular Alcohol Use

Alcohol Dependence

Cessation


Treatment of addiction today, even the best evidence-based treatment, often comes down to a trial and error process.


Genetics is here to stay
Genetics is here to stay treatment, often comes down to a trial and error process.

  • 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


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