an overview of genetic influences in alcoholism marc a. schuckit
TRANSCRIPT
AN OVERVIEW OF GENETIC INFLUENCES IN ALCOHOLISM
Marc A. Schuckit
Copyright Alcohol Medical Scholars Program
2
LECTURE REVIEWS Genetic Influences Overall
Intermediate Phenotypes
Specific Genes
Environment
COMPLEX GENETIC INFLUENCED DISORDERS
MI
Type 2 Diabetes
Cancer
GENES AND ALCOHOLISM
4 x Risk for COAs
4 x Risk for Adopted out COAs
Higher Risk for ID Twins of Alcoholics
VARIANCE OF RISK
Environment40%
Genetics60%
(Heterogeneous and Polygenic)
ENDOPHENOTYPE GENETIC
OBSERVED EARLY
PREDICTS DX
POSSIBLE FAMILIES OF RISK FACTORS
Alcohol Metabolizing Enzymes
Level of Response (LR)
Impulsivity
Psychiatric Disorders
ALCOHOL METABOLISM
Alcohol ADH Acetaldehyde
ALDH
CO2 + H2O
POSSIBLE FAMILIES OF RISK FACTORS
Alcohol Metabolizing Enzymes
Level of Response (LR)
Impulsivity
Psychiatric Disorders
LR RATIONALE Youth Drink for Effects If Need More for Effect
Will Drink More Then Heavy Drinking Affects
PeersExpectationsStress
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.
0
20
40
60
80
100
120
140
0 30 60 90 120 150 180
Time
Effe
ct
FHNFHP
.05
.01
.05.05
SRESRE TIME FRAME:
DRINKS 1st 5 Recent
HeaviestNEEDED TO: Times 3 Mos
Feel Effect
Feel Dizzy orSlur Speech
Stumble
Fall Asleep
LRLow HighCOA Jews
Native Americans Most Asians
Koreans ? Blacks
12 YEAR OLD CORRELATES
Maximum Drinks .49
Frequency .11
Problems .28
LR CORRELATES1° RELATIVES .20
2° RELATIVES .15
UNRELATED .02
FATHER/OFFSPRING (20yr) .40
TWINS h2 = .6
LR PREDICTS OUTCOME
San Diego Prospective Study
Australian Twins
Danish Adoptees
Colorado Twins
CORRELATIONS OF LR TO OUTCOME
Alcoholic Outcome
LR -.25 Control for:
FREQ -.23 QUANT -.21
BOTH -.19
SRE PREDICTS OUTCOMES
r ORMax Drinks .22 2
26 Problems .28 3
Dependence Items .25 3.5
AUD .31 2.5
ENDOPHENOTYPE GENETIC
OBSERVED EARLY
PREDICTS DX
LR60% GeneticsLR Relates to Risk
COANative AmericansKoreans
Low LR Predicts Outcome
SEARCH FOR GENES FOR LR
Association Linkage Animal Models
BACKGROUND
5 HTT Relates to drinking
AnimalsHumans
GABRA6 Animal
GENOTYPES, LR, & ALCOHOL DEPENDENCE
5HTT GABAA6 BOTH 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
Copyright Alcohol Medical Scholars Program
27
CHROMOSOME 10
CANDIDATES:ASSOCIATION
GABRA6 COMT 5HTT
GABRG2 DRD2/ANKK1 ADORA
GABRA5 DRD4 NPY
GABRA1
KCNMA1 DGKZ ADHIB
GNAS ADH1C
PK CYP2E
VARIANCE OF RISK
Environment40%
Genetics60%
(Heterogeneous and Polygenic)
“ENVIRONMENT”Child Home Expectancy
Peers Religion
Stress Coping
Fhalc
sex
age
.20
-.20 -.18
.20Fhalc
LR
HOME
.17
.29
.07
EXPECT
.25
ALC OUT.50
.49
.24
.24
POSSIBLE FAMILIES OF RISK FACTORS
Alcohol Metabolizing Enzymes
Level of Response (LR)
Impulsivity
Psychiatric Disorders
LECTURE REVIEWS
Genetic Influences OverallIntermediate PhenotypesSpecific GenesEnvironment
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