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STAGES OF QUESTIONS

STAGES OF QUESTIONS. Is it Genetic? What’s Inherited? What Are the Genes? How Does Environment Contribute?. THE IMPORTANCE OF GENETICS IS SUPPORTED BY:. Family Twin Adoption. GENETIC INFLUENCES OPERATE IN:. Choice to Drink Level of Response Reinforcement Consequences

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STAGES OF QUESTIONS

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

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

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

  4. COMPLEXITIES • Environment • Heterogeneity • Polygenic

  5. VARIANCE OF RISK (Heterogeneous and Polygenic)

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

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

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

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

  11. COMPLEXITIES • Environment • Heterogeneity • Polygenic

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

  13. SEARCH FOR GENES FOR LR • Association • Linkage • Animal Models

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

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

  16. GENOTYPES, LR, & ALCOHOL DEPENDENCE 5HTTGABAA6BOTH LL+ SS+ LLSLSSPro/SerPro/ProPro/SerPro/Pro LR %ALC -.89 -.30 00 57 21 12 -1.01 -.27 71 23 -1.29 +.03 100 00

  17. 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

  18. RESULTS ACROSS STUDIES CHROM ~cMCHALSRECOGAOTHER 1 160-190 1.6 2.0 ALCF 1 220 1.8 PROT.D 2 140 2.5 ALCF, CDD 4 60-70 1.6 EEGP, ALCR INDL , GABRB1 4 170 1.6 INDE 5 140 1.6 GABRA6 7 60-70 1.8 ALCR AC 7 100 1.8 ALCF INDE, GLUT. 10 140 2.6 2.1 11 85 1.8 4.0 22 25 3.0 ALC

  19. 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+)

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

  21. CHILD DOMAINS FH Peers Home Internalizing Social Support Externalizing Stress Puberty School SES Cognition Religiosity Expectancies Coping Self Esteem Self Efficacy

  22. General Theoretical LR Model

  23. Empirical Model - Fathers

  24. Theoretical Gene X Environment Model

  25. SERT X EXT

  26. GABA X AEQ

  27. G X E INTERACTIONS GABAA6 - ALC DEP r DTC: LOW -.08 HIGH .55 AEQ: LOW .20 HIGH .57 SERT - ALC DEP r BU: LOW 0 HIGH .33

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

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

  30. ESTABLISHING INTERACTIONS • z-Transform Predictors • Create Interaction Term • Hierarchical Regression • Enter Main Effects • Enter Interaction • Determine if Interaction Adds

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

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

  33. LR - Socialization Model GRPAR .30 PEERS PAR .37 AEQ .26 .48 .23 LR .44 .36 .67 ALC PROBS Drink Cope .65 Home .24 .22 .31 Soc Support

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

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