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STAGES OF QUESTIONS

This study explores the genetic influences on alcohol dependence, investigating the role of inherited traits, environmental contributions, and interactions between genes and environment. It delves into the complexities surrounding low levels of response to alcohol and potential risk factors, with a focus on identifying relevant genes, improving prevention strategies, and evaluating treatment approaches.

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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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