1. STAGES OF QUESTIONS n Is it Genetic? n What’s Inherited? n What Are the Genes? n How Does Environment Contribute?

2. THE IMPORTANCE OF GENETICS IS SUPPORTED BY: 4 Family 4 Twin 4 Adoption

3. GENETIC INFLUENCES OPERATE IN: Choice to Drink Level of Response Reinforcement Consequences DEPENDENCE

4. COMPLEXITIES n Environment n Heterogeneity n Polygenic

5. VARIANCE OF RISK (Heterogeneous and Polygenic)

6. POSSIBLE FAMILIES OF RISK FACTORS n Level of Response (LR) n P3 / Disinhibition / ASPD / Type 2 / B n Independent Axis II Disorders n Opioids n Alcohol Metabolizing Enzymes

7. 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.

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

10. LR 60% Heritability LR Relates to Risk COA Native Americans Koreans Jews Low LR Predicts Outcome Independent

11. OVERALL GOALS n Find Relevant Genes n Study Environment n Evaluate G x E Interactions n Improve: Prevention Treatment

12. COMPLEXITIES n Environment n Heterogeneity n Polygenic

13. DATA SOURCES SD Prospective 3 Generations Prospective Genes & Environment Alc Challenges COGA SRE UCSD/UCSF Sib-Pairs Alc Challenges

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

15. CANDIDATE GENES FOR LR 1 ST LINE 2 ND MESSENGERS NEUROTRANSMITTERS G-PROTEINS GABA A A C 5 - HT PKAs ADENOSINE NPY OTHER DA NIC/MUSC OPIOID COMT/DISC1/G72 C B CYP2E1

16. 20 YEAR SAMPLE n 440 Subjects n 365 Spouses n 550 Children (x age = 15)

17. 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

18. TESTING Subjects Acute Challenge 0.75 to 0.90 ml / kg ETOH Measure Reaction Over 3 Hours Subjective Feelings Observer Ratings Body Sway Etc. Bloods Parents Bloods & SRE

19. CHROM ~cM CHAL SRE COGA OTHER 1 160-190 1.6 2.0 ALC F 1 220 1.8 PROT. D 2 140 2.5 ALC F, CD D 4 60-70 1.6 EEG P, ALC R IND L, GABRB1 4 170 1.6 IND E 5 140 1.6 GABRA6 7 60-70 1.8 ALC R AC 7 100 1.8 ALC F IND E, GLUT. 10 140 2.6 2.1 11 85 1.8 4.0 22 25 3.0 ALC RESULTS ACROSS STUDIES

20. SAN DIEGO PROSPECTIVE STUDY BASELINE: 453 LR FH Demography Substance/Psychiatric Hx T10:453 Found Data on 449 (Including 2 Dead) T15:Data on 440 (Including 2 Dead, Total 4 Dead) 365 Spouse Interviews 444 Offspring (CBCL + CSSAGA-P; 151 Age 7+)

21. DOMAINS n Behavioral Undercontrol(BU) n Coping Style (WOC + DTC) n Stress(LES + Work Stress) n Social Support (SSQ N, S + SPS) n Expectancies (AEQ) n Drinking Environment (IPA + S pouse )

22. CHILD DOMAINS FHPeers Home InternalizingSocial Support ExternalizingStress PubertySchool SES CognitionReligiosity Expectancies Coping Self Esteem Self Efficacy

23. General Theoretical LR Model

24. Empirical Model - Fathers

25. Theoretical Gene X Environment Model

26. SERT X EXT

27. GABA X AEQ

28. G X E INTERACTIONS GABA A  - ALC DEP r  DTC: LOW -.08 HIGH.55 AEQ: LOW.20 HIGH.57 SERT - ALC DEP r BU: LOW 0 HIGH.33

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

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

31. ESTABLISHING INTERACTIONS n z-Transform Predictors n Create Interaction Term n Hierarchical Regression é Enter Main Effects é Enter Interaction n Determine if Interaction Adds

32. SRE GENOME SCAN 336 Markers (10.5 cM Intervals) Heterozygosity 0.74 745 Sib-Pairs 103 Affected Sib-Pairs

33. 811 Markers (4cM intervals) Heterozygosity > 0.70 Genotype Failure < 5% Error Rate 4.4 / 1000 Genotypes GALLO ANALYSES

34. LR - Socialization Model LR ALC PROBS GRPAR PAR Home Soc Support PEERS AEQ Drink Cope.30.23.36.24.37.22.31.65.44.48.67.26

35. CRITERIA n 18 - 25 Years Old n Non-Asian n Drinker n Not Alcohol Dependent n Not ASPD, Bipolar, or Schizophrenic n Has Alcoholic Parent n Available Sib