1. Genetics of Alcoholism Laura Jean Bierut, MD Washington University

2. 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.

7. 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.

8. Evidence for Genetic Factors Adoptees and biologic relatives Twins - Monozygotic and Dizygotic

9. Adoption Studies

10. Adoptive Parents Biologic Parents Adopted Child

11. Understanding Genetic and Environmental Influences Using Twin Studies

12. 100% genes 100% home environment Monozygotic Twins

13. Understanding Genetic and Environmental Influences Using Twin Studies 100% genes 100% home environment Monozygotic TwinsDizygotic Twins 50% genes 100% home environment

14. Understanding Genetic and Environmental Influences Using Twin Studies 100% genes 100% home environment Monozygotic TwinsDizygotic Twins 50% genes 100% home environment We are a combination of our genes and environment.

15. Alcohol Dependence - A many step process Initiation

16. Alcohol Dependence - A many step process Initiation Regular alcohol use

17. Alcohol Dependence - A many step process Initiation Regular alcohol use Alcohol Dependence

18. 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.

19. Theta + Delta Oscillations Underlying GO NO-GO P3 Are Reduced In Alcoholics THETA DELTA Kamarajan et al., 2003 Alcoholic Control P3

20. 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 (blue) Eye Color Gene (brown) Tongue Roller Gene (roller) Tongue Roller Gene (non-roller) Hair Color Gene (dark) Hair Color Gene (blonde)

21. Approaches to Genetic Studies Candidate gene examination - Family based or case control approach Hypothesis driven Whole genome approach Generally case control approach Hypothesis free

22. COGA Collaborative 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

23. Genetic Strategy 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 AGene BGene C

24. Genes Associated with Alcoholism ALDHAldehyde metabolism ADH4Alcohol metabolism GABRA2 And many others Gaba receptor

25. Association strategy Multiple analytic methods Multiple genetic variants in each gene Examination across the region Consistency of results

26. 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.

27. Cessation- The Final Step Initiation Regular Alcohol Use Alcohol Dependence Cessation

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

29. 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