1. Alcohol & other addictions: can DNA make a difference? Dr Martin Kennedy Department of Pathology Christchurch School of Medicine & Health Sciences University of Otago

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

4. Genes 101

5. DNA, chromosomes & genes

6. Chromosome structure

7. Chromosomal DNA

8. Complex disorders 101

9. Genes x Environment

10. Genetics contributes to most conditions Genetics Environment cystic fibrosis Genetics Environment AIDS Genetics Environment coronary artery disease

11. Genetics Environment cystic fibrosis Genetics Environment AIDS Genetics Environment depression Genetics contributes to most conditions

12. Genetics Environment cystic fibrosis Genetics Environment AIDS Genetics Environment addiction? Genetics contributes to most conditions

13. Risk factors for complex disease Environment Genes

14. “Disease genes” (alleles)

15. Common genetic variants n Single nucleotide polymorphisms (SNPs) n Each of us has about 2-3 million of these n Many other less common variants u VNTRs u Microsatellites u Deletions/insertions etc

16. Are there genes for addiction?

17. Genetic epidemiology n The pattern of incidence in families and the population: u Family studies u Twin studies u Adoption studies

18. Family studies of substance abuse disorders n Familial aggregation of alcoholism well established n Increasing empirical research that drug-use disorders also familial n Estimated 8-fold increased risk of drug disorders in relatives

20. Concordance in twin studies McGuffin (1999)

21. Alcoholism in twins Concordance Rate Dizygotic (non-identical) 10-15% Monozygotic (identical) 30-40%

22. Other evidence n Numerous twin studies indicate genetic factors in substance-use disorders. n Adoption studies provide strong support for genetic influences in liability to drug abuse.

23. Insights from animal studies

24. Flies MAY hold SOME clues to ASPECTS of alcoholism

26. Animal models of addiction n Genetic models are partial n Each addresses one or more of the contributing traits rather than the disorder as a whole, e.g. u reward u tolerance u pathological effects n Rodent gene mapping studies

27. What might these genes do?

28. Candidate “addiction” genes n brain reward systems (e.g. dopamine pathways) n endogenous opioid system n drug metabolism, uptake etc n and many others, some no doubt surprising! Likely to function in:

29. How will we find these genes?

30. 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

31. Disease gene mapping n Association studies u using DNA markers to ask whether a particular gene variant is more commonly associated with occurrence of a disease n Linkage mapping u using “DNA markers” to find the chromosomal location of a disease gene n By implication in relevant behavioural processes in animal models n Genes of major effect

32. Genome scan results

34. What might these genes be used for?

35. Potential uses of genes n New avenues by which to explore the biology of the condition n Research tools n Improved medications u Tailored treatment (pharmacogenetics) u New drug leads n Risk prediction? Time

36. 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

37. 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

38. Can genes make a difference? A qualified “yes”: n Improved biological knowledge n Research tools n Tailored therapeutic drug prescribing n Long term investment (planning for the future)

39. Will genes change the lives of practioners or consumers? n Not anytime soon! n But new knowledge will eventually lead to changes in practice

40. Please don’t pay much attention to those headlines!

41. Genes control biology, not behaviour.