STAGES OF QUESTIONS Is it Genetic? Whats 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 DrinkLevel of ResponseReinforcement

Consequences

DEPENDENCE

COMPLEXITIES Environment Heterogeneity Polygenic

VARIANCE OF RISK(Heterogeneous and Polygenic)

POSSIBLE FAMILIES OF RISK FACTORSLevel of Response (LR)P3 / Disinhibition / ASPD / Type 2 / BIndependent Axis II DisordersOpioidsAlcohol 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.

Chart1

00

13599

12595

12079

9059

7042

3934

.05

.01

.05

.05

FHN

FHP

Time Post-Ethanol Administration (minutes)

SHAS Total Score

Breath Alcohol Bar Chart

30 MinStdNt

FHP Rapid0.0833750.024486416-0.0656766083

FHP Slow0.0771290.028329931

FHN Rapid0.08171430.024000322-0.0072152988

FHN Slow0.080920.022229725

Breath Alcohol Bar Chart

00.0244864

00.0283299

00.0240003

00.0222297

30 Min

Breath Alcohol Level

Blood Alcohol Level for Rapid and Slow FHP and FHN subjects at 30 Minutes

Fast Data

0

0

0

0

30 Min

Breath Alcohol Level

Blood Alcohol Level for Rapid and Slow FHP and FHN subjects at 30 Minutes

Graph

0Alcohol16EBA160000

7E30160.0833750.02448640.0430.131

30E60160.08806250.01342870.0610.109

60E90160.08006250.01070490.0580.099

90E120160.07031250.00972780.0510.088

120E150160.0618750.00882330.0470.081

150E180160.05531250.00847520.0410.076

180E210160.0486250.01167830.030.081

210PHIGHBA160000

PHIGH71611.812511.3502937036

PHIGH301614.510.198039236

PHIGH601612.7510.705139036

PHIGH901610.06259.8689327131

PHIGH120168.1257.804913029

PHIGH150165.256.8361783023

PHIGH1801635.6803756020

FHPMenAlcohol16PHIGH210161.68753.5160347014

PDRUGBA160000

PDRUG71613.513.3516541036

PDRUG30161410.9726934036

PDRUG601613.7511.0664659036

PDRUG9016108.9666047030

PDRUG120166.8756.8300805025

PDRUG150165.1256.1846584018

PDRUG180163.3754.8287334017

PDRUG210161.753.0659419011

shastba160000

shast71670.312573.50439330223

shast301682.12562.42101688243

shast601673.812566.585502710241

shast901657.2554.56922216197

shast1201638.539.54238231152

shast1501629.062537.10609790127

shast1801616.937529.1786880116

shast21016915.1789328061

Alcohol21EBA210000

E30210.08171430.02400030.0430.144

E60210.09066670.01118630.0640.113

E90210.08080950.00855350.0660.098

E120210.0693810.00872630.0570.084

E150210.06019050.00832840.0470.076

E180210.05323810.00795550.0420.066

E210210.04566670.00885060.030.06

PHIGHBA210000

PHIGH7213.85714294.6398892016

PHIGH30216.57142865.0355876020

PHIGH60216.90476195.0289637220

PHIGH90214.66666674.7679485020

PHIGH120212.80952382.694792208

PHIGH150211.66666672.129162606

PHIGH180210.85714291.388730104

PHIGH210210.38095240.804747803

PDRUGBA210000

PDRUG7215.09523817.9680911032

PDRUG30218.19047627.447275031

PDRUG60219.38095246.8809606228

PDRUG90217.23809526.5261379126

PDRUG120214.71428574.9914212021

PDRUG150213.71428574.8181206019

PDRUG180211.61904761.596126305

PDRUG210210.80952381.600595106

shastba210000

shast72127.380952443.92661630180

shast302144.761904848.30104013211

shast60215246.24932437186

shast902136.476190540.26613843165

shast1202125.428571429.83047340130

shast1502116.619047626.36944480119

shast180217.09523818.9493283031

shast210212.9523814.598654016

Data

Data

00

13599

12595

12079

9059

7042

3934

.05

.01

.05

.05

FHN

FHP

Time Post-Ethanol Administration (minutes)

SHAS Total Score

AverageFHPFHN

000

3099135

6095125

9079120

1205990

1504270

1803439

SRE TIME FRAME: DRINKS 1st 5 Recent HeaviestNEEDED TO: Times 3 MosFeel EffectFeel Dizzy orSlur SpeechStumbleFall Asleep

LR60% HeritabilityLR Relates to RiskCOANative AmericansKoreansJewsLow LR Predicts OutcomeIndependent

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

COMPLEXITIES Environment Heterogeneity Polygenic

DATA SOURCESSD Prospective 3 Generations Prospective Genes & EnvironmentAlc Challenges

COGASRE

UCSD/UCSFSib-PairsAlc Challenges

SEARCH FOR GENES FOR LR Association Linkage Animal Models

CANDIDATE GENES FOR LR1ST 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

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

GENOTYPES, LR, & ALCOHOL DEPENDENCE5HTTGABAA6BOTH LL+ SS+ LL SL SS Pro/Ser Pro/Pro Pro/Ser Pro/ProLR

%ALC-.89 -.30 00

57 21 12-1.01 -.27

71 23-1.29 +.03

100 00

TESTINGSubjectsAcute Challenge 0.75 to 0.90 ml / kg ETOHMeasure Reaction Over 3 HoursSubjective FeelingsObserver RatingsBody SwayEtc.BloodsParentsBloods & SRE

RESULTS ACROSS STUDIESCHROM ~cM CHAL SRE COGA OTHER 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

SAN DIEGO PROSPECTIVE STUDYBASELINE: 453LRFHDemographySubstance/Psychiatric Hx

T10:453 FoundData on 449 (Including 2 Dead)

T15:Data on 440 (Including 2 Dead, Total 4 Dead)365 Spouse Interviews444 Offspring (CBCL + CSSAGA-P; 151 Age 7+)

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

CHILD DOMAINSFHPeersHomeInternalizingSocial SupportExternalizingStressPubertySchoolSESCognitionReligiosityExpectanciesCopingSelf Esteem Self Efficacy

General Theoretical LR Model

_1117260089.doc

(Home)

ALC

LR

Drink in

Env

AEQ

FHalc

EXT

COPE

Empirical Model - Fathers

_1117260575.doc

(Home)

ALC

LR

Drink in

Env

AEQ

FHalc

EXT

COPE

.16

.18

.14

.14

.12

.10

.23

.11

.01

.29

.15

Theoretical Gene X Environment Model

_1117261142.doc

ALC

Gene

Environ

FHalc

SERT X EXT

_1117261581.doc

ALC

SERT

EXT

FHalc

.28

.48

.31

GABA X AEQ

_1117261428.doc

ALC

GABA

AEQ

FHalc

.18

.32

.32

G X E INTERACTIONS GABAA6 - ALC DEP r DTC: LOW -.08 HIGH .55

AEQ: LOW .20 HIGH .57

SERT - ALC DEP r

BU: LOW 0 HIGH .33

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

IMPLICATIONS FOR TREATMENTDevelop Rx for Specific Risk Factors Evaluate Rx Separately in Subgroups

ESTABLISHING INTERACTIONS z-Transform Predictors Create Interaction Term Hierarchical Regression Enter Main Effects Enter Interaction

Determine if Interaction Adds

SRE GENOME SCAN336 Markers (10.5 cM Intervals)Heterozygosity 0.74745 Sib-Pairs103 Affected Sib-Pairs

GALLO ANALYSES811 Markers (4cM intervals)Heterozygosity > 0.70Genotype Failure < 5%Error Rate 4.4 / 1000 Genotypes

LR - Socialization ModelLRALC PROBSGRPARPARHomeSocSupportPEERSAEQDrinkCope.30.23.36.24.37.22.31.65.44.48.67.26

CRITERIA18 - 25 Years OldNon-AsianDrinkerNot Alcohol DependentNot ASPD, Bipolar, or SchizophrenicHas Alcoholic ParentAvailable Sib