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

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

Adoptees and biologic relatives

Twins - Monozygotic and Dizygotic

Adoption Studies

Adoption Studies

Adoptive Parents Biologic Parents

Adopted Child

Understanding Genetic and Environmental Influences Using Twin Studies

Understanding Genetic and Environmental Influences Using Twin Studies

100% genes100% home environment

Monozygotic Twins

Understanding Genetic and Environmental Influences Using Twin Studies

100% genes100% home environment

Monozygotic Twins Dizygotic Twins

50% genes100% home environment

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.

Alcohol Dependence - A many step process

Initiation

Alcohol Dependence - A many step process

Initiation

Regular alcohol use

Alcohol Dependence - A many step process

Initiation

Regular alcohol use

Alcohol Dependence

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.

Theta + Delta Oscillations UnderlyingGO NO-GO P3 Are Reduced In Alcoholics

THETA DELTA

Kamarajan et al., 2003

Alcoholic

Control

P3

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)

Approaches to Genetic Studies

Candidate gene examination -

Family based or case control approach

Hypothesis driven

Whole genome approach

Generally case control approach

Hypothesis free

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

Genetic Strategy

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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

Genes Associated with Alcoholism

ALDH Aldehyde metabolism

ADH4 Alcohol metabolism

GABRA2

And many others

Gaba receptor

Association strategy

Multiple analytic methods

Multiple genetic variants in each gene

Examination across the region

Consistency of results

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.

Cessation- The 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

Genetic findings open valuable possibilities for the future of medicineGreater understanding of biologic

pathways is disorders.Understanding of environmental influencesNew targets for personalized medicine