Transcript CANDIDATE GENES FOR LR - Home | California Society of

STAGES OF QUESTIONS

Is it Genetic?

What’s 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 Drink
Level of Response
Reinforcement
Consequences
DEPENDENCE
COMPLEXITIES
Environment
 Heterogeneity
 Polygenic

VARIANCE OF RISK
Environment
40%
Genetics
60%
(Heterogeneous and Polygenic)
POSSIBLE FAMILIES OF
RISK FACTORS
 Level
 P3
of Response (LR)
/ Disinhibition / ASPD / Type 2 / B
 Independent
Axis II Disorders
 Opioids
 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.
SHAS Total Score
140
.05
120
.05
100
FHN
FHP
.01
80
60
40
20
0
0
30
60
90
120
150
Time Post-Ethanol Administration (minutes)
180
SRE
TIME FRAME:
DRINKS
NEEDED TO:
Feel Effect
Feel Dizzy or
Slur Speech
Stumble
Fall Asleep
1st 5
Times
Recent
3 Mos
Heaviest
LR
60% Heritability
LR Relates to Risk
COA
Native Americans
Koreans
Jews
Low LR Predicts Outcome
Independent
OVERALL GOALS

Find Relevant Genes

Study Environment

Evaluate G x E Interactions

Improve: Prevention
Treatment
COMPLEXITIES
Environment
 Heterogeneity
 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
Association
 Linkage
 Animal Models

CANDIDATE GENES
FOR LR
1ST LINE
2ND MESSENGERS
G-PROTEINS
AC
PKAs
NEUROTRANSMITTERS
GABAA
5 - HT
ADENOSINE
NPY
OTHER
DA
OPIOID
CB
NIC/MUSC
COMT/DISC1/G72
CYP2E1
20 YEAR SAMPLE

440 Subjects

365 Spouses

550 Children (x age = 15)
GENOTYPES, LR, &
ALCOHOL DEPENDENCE
5HTT
LL
LR
%ALC
SL
-.89 -.30
57
21
GABAA6
SS
BOTH
LL+
SS+
Pro/Ser Pro/Pro Pro/Ser Pro/Pro
00
-1.01
-.27
-1.29
+.03
12
71
23
100
00
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
RESULTS ACROSS
STUDIES
CHROM
~cM
CHAL SRE
1
1
2
4
160-190
220
140
60-70
1.6
1.8
2.5
1.6
4
5
7
170
140
60-70
1.6
1.6
1.8
7
10
11
22
100
140
85
25
1.8
2.6
1.8
3.0
2.0
COGA
OTHER
ALCF
PROT.D
ALCF, CDD
EEGP, ALCR
INDL , GABRB1
ALCR
ALCF
2.1
4.0
ALC
INDE
GABRA6
AC
INDE, GLUT.
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

Behavioral Undercontrol (BU)

Coping Style (WOC + DTC)

Stress (LES + Work Stress)

Social Support (SSQ N, S + SPS)

Expectancies (AEQ)

Drinking Environment (IPA + Spouse)
CHILD DOMAINS
FH
Internalizing
Externalizing
Puberty
Cognition
Expectancies
Coping
Self Esteem
Self Efficacy
Peers
Home
Social Support
Stress
School
SES
Religiosity
EXT
Drink in
Env
FHalc
LR
AEQ
ALC
(Home)
COPE
General Theoretical LR Model
.29
.10
EXT
Drink in
Env
FHalc
.16
.14
.01
.15
.11
AEQ
LR
.18
ALC
.23
.12
(Home)
COPE
.14
Empirical Model - Fathers
Environ
FHalc
Gene
ALC
Theoretical Gene X Environment Model
EXT
FHalc
.31
.48
SERT
.28
SERT X EXT
ALC
AEQ
FHalc
.32
.32
GABA
.18
GABA X AEQ
ALC
G X E INTERACTIONS
GABAA6 - ALC DEP r
DTC: LOW
HIGH
-.08
.55
AEQ: LOW
HIGH
.20
.57
SERT - ALC DEP r
BU:
LOW
HIGH
0
.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

z-Transform Predictors

Create Interaction Term

Hierarchical Regression
 Enter Main Effects
 Enter Interaction

Determine if Interaction Adds
SRE GENOME SCAN
336 Markers (10.5 cM Intervals)
Heterozygosity 0.74
745 Sib-Pairs
103 Affected Sib-Pairs
GALLO ANALYSES
811 Markers (4cM intervals)
Heterozygosity > 0.70
Genotype Failure < 5%
Error Rate 4.4 / 1000 Genotypes
LR - Socialization Model
GRPAR
.30
PEERS
PAR
.37
.23
.26
AEQ
LR
.36
.44
ALC
PROBS
.67
Drink
Cope
Home
.24
.48
.22
Soc
Support
.65
.31
CRITERIA

18 - 25 Years Old

Non-Asian

Drinker

Not Alcohol Dependent

Not ASPD, Bipolar, or Schizophrenic

Has Alcoholic Parent

Available Sib