1. AN OVERVIEW OF GENETIC INFLUENCES IN ALCOHOLISM Marc A. Schuckit

2. Copyright Alcohol Medical Scholars Program 2

3. LECTURE REVIEWS Genetic Influences Overall Intermediate Phenotypes Specific Genes Environment

4. COMPLEX GENETIC INFLUENCED DISORDERS MI Type 2 Diabetes Cancer

5. GENES AND ALCOHOLISM 4 x  Risk for COAs 4 x  Risk for Adopted out COAs Higher Risk for ID Twins of Alcoholics

6. VARIANCE OF RISK (Heterogeneous and Polygenic)

7. ENDOPHENOTYPE  GENETIC  OBSERVED EARLY  PREDICTS DX

8. POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

9. ALCOHOL METABOLISM Alcohol ADH Acetaldehyde ALDH CO 2 + H 2 O

10. POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

12. LR RATIONALE Youth Drink for Effects If Need More for Effect Will Drink More Then Heavy Drinking Affects Peers Expectations Stress

13. LOW LEVEL OF RESPONSE TO ALCOHOL (LR) 1.Less Alcohol Related Change on a Challenge. 2.The Need for a Relatively High Number of Drinks for an Effect.

15. SRE TIME FRAME: DRINKS 1st 5 Recent Heaviest NEEDED TO: Times 3 Mos Feel Effect Feel Dizzy or Slur Speech Stumble Fall Asleep

16. LR LowHigh COAJews Native Americans Most Asians Koreans? Blacks

17. 12 YEAR OLD CORRELATES Maximum Drinks.49 Frequency.11 Problems.28

18. LR CORRELATES 1° RELATIVES.20 2° RELATIVES.15 UNRELATED.02 FATHER/OFFSPRING (20yr).40 TWINS h 2 =.6

19. LR PREDICTS OUTCOME San Diego Prospective Study Australian Twins Danish Adoptees Colorado Twins

20. CORRELATIONS OF LR TO OUTCOME Alcoholic Outcome LR-.25 Control for: FREQ-.23 QUANT-.21 BOTH-.19

21. SRE PREDICTS OUTCOMES rOR Max Drinks.22 2 26 Problems.28 3 Dependence Items.25 3.5 AUD.31 2.5

22. ENDOPHENOTYPE  GENETIC  OBSERVED EARLY  PREDICTS DX

23. LR 60% Genetics LR Relates to Risk COA Native Americans Koreans Low LR Predicts Outcome

24. SEARCH FOR GENES FOR LR n Association n Linkage n Animal Models

25. BACKGROUND 5 HTT Relates to drinking  Animals  Humans GABRA6 Animal

26. GENOTYPES, LR, & ALCOHOL DEPENDENCE 5HTTGABA A  6 BOTH LL+ SS+ LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/Pro LR %ALC -.89 -.30 00 57 21 12 -1.01 -.27 71 23 -1.29 +.03 100 00

27. Copyright Alcohol Medical Scholars Program 27 CHROMOSOME 10

29. CANDIDATES: ASSOCIATION GABRA6COMT5HTT GABRG2DRD2/ANKK1 ADORA GABRA5DRD4 NPY GABRA1 KCNMA1DGKZ ADHIB GNAS ADH1C PK CYP2E

30. VARIANCE OF RISK (Heterogeneous and Polygenic)

31. “ENVIRONMENT” Child Home Expectancy Peers Religion Stress Coping

32. Fhalc sex age.20 -.20 -.18.20 Fhalc LR HOME.17.29.07 EXPECT.25 ALC OUT.50.49.24

33. POSSIBLE FAMILIES OF RISK FACTORS n Alcohol Metabolizing Enzymes n Level of Response (LR) n Impulsivity n Psychiatric Disorders

34. LECTURE REVIEWS Genetic Influences Overall Intermediate Phenotypes Specific Genes Environment

36. IMPLICATIONS FOR PREVENTION Enhance Education of Vulnerabilities Find Environmental / Psychosocial Protective Factors Specific to Risk

37. IMPLICATIONS FOR TREATMENT Develop Rx for Specific Risk Factors Evaluate Rx Separately in Subgroups