Assessing Predisposition to Alcoholism and Recovery

1. Assessing Predisposition to Alcoholism and Recovery John Pankiewicz, M.D.

2. Audience Response Present science indicates genetics explain what percentage of vulnerability to alcoholism? A. 20% B. 30% C. 45% D. 50%

3. Alcoholism Definitions Alcohol Abuse (one or more of the following) Failure to fulfill major role obligations at home,work, or school e.g. absence Hazardous use e.g. driving Alcohol related legal problems Social/Interpersonal problems Alcohol Dependence-More physiologic issues (3 or more of the following) Tolerance - Takes more to get drunk Withdrawal - Physical symptoms that drinking will quell Desire or failed efforts to cut down Spend more time in drinking activities Important activities given up - social, work, hobbies Continued use despite knowledge

4. Alcoholism in U.S. Recent data showed 8.6% prevalence of dependence and abuse in U.S. Estimates indicate 75% of US population Drinks Approximately 25 Million people Probably an under-estimate given under reporting of drinking behavior Associated with substantial proportion of Domestic Violence, Child Abuse, General Crimes

5. Heredity and Genetics Conditions like alcoholism noted to run in families Led to twin, adoption and family studies 50 plus % attributable to inheritance Heterogenic* Non-Mendelian - Clearly not entirely genetic or single cause

6. Heredity 10,000 twin pairs studied- Concordance Alcoholism - 0.5 Generalized Anxiety Disorder - 0.32 Autism - 0.9 Initially thought to be more heritable in males Newest data indicates risk is equal for men and women

7. Gene Functions Genes create 100,000 different proteins Addiction Enzymes responsible for drug metabolism (breakdown or conversion) Neurochemical action - effect neurotransmitters or receptors

8. Gene Identification Flushing Phenomenon - First gene identified related to alcohol Noted in Asian populations Aldehyde Dehydrogenase is slower ALDH1 gene 44% Japanese 53% Vietnamese 45% Han Chinese Rare in Europeans Confers 6 Fold reduction in alcoholism risk Alcohol Dehydrogenase - First step in alcohol breakdown ADH4 variants- Confers faster alcohol conversion Increased risk for alcoholism

9. Gene Search-Genome Association Full genetic sequence of large population groups Compare genetics of those with and without disease Difficult to do because of need for large numbers to increase statistical power

10. Gene Search-Genome linkage Full genetic sequence of high risk families Identify shared genetics in those with and without alcoholism Works best in large, “isolated” families - Reduces genetic hetorogeneity

11. Gene Search Definitions Phenotype -Traits expressed by genes e.g. blue eyes, A positive blood type Endophenotype - Physical traits not externally visible, but measurable e.g. Task specific MRI, EEG, electrophysiologic measures

12. Gene Search-Endophenotype Better than behavioral symptoms due to quantification Useful in “distilling” alcoholic families Found linkage to Chromosomes 1,2,4 and 7 Specific genes associated with: Alcohol Dehydrogenese GABA-Neurotransmitter Cholinergic Receptors