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

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

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

COMPLEXITIES n Environment n Heterogeneity n Polygenic

VARIANCE OF RISK (Heterogeneous and Polygenic)

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

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.

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

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

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

COMPLEXITIES n Environment n Heterogeneity n Polygenic

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

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

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

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

GENOTYPES, LR, & ALCOHOL DEPENDENCE 5HTTGABA A  6 BOTH LL+ SS+ LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/Pro LR %ALC

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

CHROM ~cM CHAL SRE COGA OTHER ALC F PROT. D ALC F, CD D EEG P, ALC R IND L, GABRB IND E GABRA ALC R AC ALC F IND E, GLUT ALC RESULTS ACROSS STUDIES

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+)

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 )

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

General Theoretical LR Model

Empirical Model - Fathers

Theoretical Gene X Environment Model

SERT X EXT

GABA X AEQ

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

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

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

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

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

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

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

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