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