Alcohol & other addictions: can DNA make a difference?

Dr Martin KennedyDepartment of PathologyChristchurch School of Medicine & Health SciencesUniversity of Otago

Topics:

Genes 101 Complex disorders 101 Are there genes for addiction? What might they do? How will we find them? What might they be used for?

Genes 101

DNA, chromosomes & genes

Chromosome structure

Chromosomal

DNA

Complex disorders 101

Genes x Environment

Genetics contributes to most conditions

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDS

Genetics

Environment

coronary artery disease

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDS

Genetics

Environment

depression

Genetics contributes to most conditions

Genetics

Environment

cystic fibrosis

Genetics

Environment

AIDS

Genetics

Environment

addiction?

Genetics contributes to most conditions

Risk factors for complex disease

Environment Genes

“Disease genes” (alleles)

Common genetic variants

Single nucleotide polymorphisms (SNPs) Each of us has about 2-3 million of these Many other less common variants

VNTRs Microsatellites Deletions/insertions etc

Are there genes for addiction?

Genetic epidemiology The pattern of incidence in families

and the population: Family studies Twin studies Adoption studies

Family studies of substance abuse disorders

Familial aggregation of alcoholism well established

Increasing empirical research that drug-use disorders also familial

Estimated 8-fold increased risk of drug disorders in relatives

Concordance in twin studies

McGuffin (1999)

Alcoholism in twins

Concordance Rate

Dizygotic (non-identical) 10-15%

Monozygotic (identical) 30-40%

Other evidence

Numerous twin studies indicate genetic factors in substance-use disorders.

Adoption studies provide strong support for genetic influences in liability to drug abuse.

Insights from animal studies

Flies MAY hold SOME clues to ASPECTS of alcoholism

Animal models of addiction Genetic models are partial Each addresses one or more of the

contributing traits rather than the disorder as a whole, e.g. reward tolerance pathological effects

Rodent gene mapping studies

What might these genes do?

Candidate “addiction” genes

brain reward systems (e.g. dopamine pathways)

endogenous opioid system drug metabolism, uptake etc and many others, some no

doubt surprising!

Likely to function in:

How will we find these genes?

The Human Genome

“This scaffold has been handed down to us from our ancestors, and through it we are connected to all other life on earth.”

Svante Pääbo, 2001

Disease gene mapping

Association studies using DNA markers to ask whether a particular gene

variant is more commonly associated with occurrence of a disease

Linkage mapping using “DNA markers” to find the chromosomal location

of a disease gene By implication in relevant behavioural processes in

animal models Genes of major effect

Genome scan results

What might these genes be used for?

Potential uses of genes

New avenues by which to explore the biology of the condition Research tools Improved medications

Tailored treatment (pharmacogenetics) New drug leads

Risk prediction?

Time

My genes made me do it...

“...promoting the identification of susceptibility genes may ... have a negative impact by diminishing the perception of the importance of individual choice in health behavior.”

Merikangas & Risch, 2004

Less knowledge is not an option

“.. we would construe it as unethical to exclude people with a mental disorder from the possibility of benefit arising from an improved understanding of mental disorders.”

Nuffield Bioethics Council Report, 1998

Can genes make a difference?

A qualified “yes”:

Improved biological knowledge Research tools Tailored therapeutic drug prescribing Long term investment (planning for the future)

Will genes change the lives of practioners or consumers?

Not anytime soon! But new knowledge will eventually lead to changes in practice

Please don’t pay much attention to those headlines!

Genes control biology, not behaviour.