Tobacco Use and Dependence Phenotypes:

1
Tobacco Use and Dependence Phenotypes What is
Heritable? Raymond Niaura, Ph.D. Jeanne
McCaffery, Ph.D, Centers for Behavioral
Preventive Medicine Department of Psychiatry
Human Behavior
Brown Medical School
2
Genetic Studies General Comment and
Overview Developments in identifying the genetic
basis for some apparently complex diseases only
emerged after identification of highly heritable
homotypic forms of these disorders based on
careful family studies (e.g., breast cancer
Alzheimers disease) Efforts to apply the same
strategies to complex human behaviors have not
been successful in light of etiologic
heterogeneity, large number of genes underlying
components of behavior, and strong environmental
influences that are likely to characterize these
phenotypes.
3
Genetic Epidemiology of Smoking Twin
Studies Eight twin studies of smoking (reviewed
by Kendler , 1998). The average concordance rate
for smoking among 891 monozygotic twin pairs was
.74 compared to that of .56 for the 1072
dizygotic twin pairs, with a broad heritability
of about .36. Twin studies of regular smoking
have yielded a greater heritability estimate of
about .54. A more recent formal twin study of
nicotine dependence in a community based sample
of female twins showed heritability of about
.70 (Kendler et al., 2000).
4
Genetic Epidemiology of Smoking Twin Studies
(continued) Genetic factors appear to exert
greater influence on the more severe forms of
smoking behavior including persistence and
dependence. BUT, little is known about early
stages of initiation, experimentation, adoption,
etc., in relation to subsequent persistence of
use. Additional sources of complexity of genetic
influences sex differences, cohort effects, and
common environmental influences that may be
sex-specific (Heath et al, 1993). The few
studies of genetic and social influences on
smoking among adolescent twins show strong
environmental influences which outweigh those of
genes (Boomsma, 1994).
5
Genetic Epidemiology of Smoking Twin Studies
(continued) Results of twin studies
consistently demonstrate that genetic factors
influence smoking to a moderate degree, with a
stronger influence on the transition to regular
smoking than on initiation (Kaprio et al, 1982
Heath and Martin, 1993).
6
How do genetic (twin) studies help us
understand environmental influences? - They
isolate the variance attributable to genetic
factors. - Certain designs can tell us about
the amount of shared (e.g., presumed familial)
and unique environmental influences. - They
fall short in (a) sometimes underestimating the
influence of the environment (b)
environmental influences per se (e.g., peer
modeling) are not typically assessed, so we
are left to guess what the environment is
actually doing (c) they tell us little about
gene-by-environment interactions
7
Genetic Epidemiology of Smoking Family Studies
of Smoking There are hardly any controlled
family study of any aspect of smoking using
traditional family study methods. There are
already numerous studies of genetic linkage and
association for smoking phenotypes that may
suffer without the basic preliminary data
required to reduce sources of complexity such as
gene-environment interaction, the number of genes
involved, the most heritable components of
nicotine outcomes, sex differences in familial
aggregation. Data on parental and sibling
influences are derived from large questionnaire
studies which examine a limited range of smoking
behaviors, (current or lifetime nicotine use),
and few interviewed more than one family.
8
Genetic Epidemiology of Smoking Family Studies
of Smoking (cont.) Most studies looked at a
range of psychosocial risk factors for smoking,
and were not designed to look at intrafamilial
patterns of nicotine-related variables. Findings
from family study data raise questions regarding
confounding of environmental factors that require
resolution before meaningful models of the
specific role of genes in smoking etiology can be
tested. E.g., Peer correlations are often larger
than sibling correlations Spouse correlations
are often greater than those between biologic
relatives Parent-offspring correlations are
often non significant after controlling for other
(e.g., peer) significant influences on adolescent
smoking.
9
Genetic Epidemiology of Smoking Family Studies
of Smoking (cont.) These findings indicate the
importance of environmental influences on
exposure and continued use of nicotine. Valid
models of risk factors for nicotine dependence
must integrate both specific environmental
influences as well as host susceptibility.
10
Genetic Epidemiology of Smoking Family Studies
of Smoking (cont.) Neither the twin nor family
designs have been fully exploited in identifying
the components nicotine use that may be
heritable, nor in investigating specific
environmental factors that may interact with
genetic susceptibility to enhance smoking
risk. Major sources of complexity so far
Sex-specific transmission (Edwards et al, 1995
Heath et al., 1995) Co-aggregation of smoking
behavior with depression, personality traits, and
alcohol use/abuse and other heritable traits that
may be associated with smoking (Heath et
al.,1995) Common environmental influences that
may interact with genetic propensity to the
initiation, persistence or cessation from smoking
(Heath and Martin 1993).
11
Classification of Tobacco Use and Dependence
Phenotypes
Class I Phenotypes Broad summary of
cross-sectional measures of smoking behavior,
e.g., ever/never smoker current/former/never-smok
er age at smoking initiation cigarettes smoked
per day.
Class II Phenotypes Cross-sectional measures of
nicotine dependence, e.g., Fagerstrom Tolerance
Questionnaire DSM criteria (symptoms).
Class III Phenotypes Longitudinal assessments
that emphasize the process of progression toward
development of regular smoking and nicotine
dependence.
12
(No Transcript)
13
(No Transcript)
14
(No Transcript)
15
Fagerstrom Tolerance Questionnaire
Items Components Analysis Total Variance
Explained Component R2 Cumulative
R2 1 21.500 21.500 2 17.406 38.905 3 12.95
4 51.860
16
Fagerstrom Tolerance Questionnaire Items Rotated
Component Matrix (N450)
Component 1 2 3 Number cigs per
day .685 Difficult in forbidden places .643
Smoke if you are ill .605 Minutes after
waking -.550 -.534 Do you inhale .393
Which cig hate to give up .720 Smoke more
in first 2 hrs .718 Nicotine content
.946 Extraction Method Principal Component
Analysis. Rotation Method Varimax with Kaiser
Normalization.
17
(No Transcript)
18
DSM IV-R Items Components Analysis
Total Variance Explained (N450)
Component R2 Cumulative
R2 1 20.809 20.809 2 17.952 38.762 3
16.251 55.013
19
DSM IV-R Items Rotated Component Matrix
(N450) Component 1 2
3 Tolerance .793 Use gt intended .671
Use despite problems .588 gt Time
obtaining/using .769 Sacrifice other
activities .734 Unable to quit/cut down
.782 Withdrawal symptoms .690 Extraction
Method Principal Component Analysis. Rotation
Method Varimax with Kaiser Normalization.
20
Pearson Correlations of FTQ and DSM Factor Scores
(n450) F1 F2 F3 D1 D2 FTQ factor score 1
(heaviness/nicotine) FTQ factor score 2 .00
(early dosing) FTQ factor score 3
.01 .00 (nicotine content) DSM factor score 1
.16 .07 .01 (Tolerance/persistence) DSM factor
score 2 .28 .06 -.08 .00 (obsessive use) DSM
factor score 3 -.03 .06 .10 .00 .00 (withdrawa
l/quitting)
21
Comparison of the Relationship of FTND With
Smoking Cessation and Major Depression (Breslau
et al., 2000)
22
Comparison of the Relationship of DSM III-R
Nicotine Dependence With Smoking Cessation and
Major Depression (Breslau et al., 2000)
23
(No Transcript)
24
Progression of Nicotine Dependence (ND) Unitary
Dimension
ND
ND
ND
T2
T3
T1
25
Progression of Nicotine Dependence (ND) Multiple
Dimensions With Sequential Entrainment
ND1
ND1
ND1
ND2
ND2
ND3
T2
T3
T1
26
Progression of Nicotine Dependence (ND) and
Psychiatric Comorbidity Complex
Phenotype MDDMajor Depressive Disorder
ADHDAttention Deficit Hyperactivity Disorder
MDD
MDD
MDD
ND
ND
ND
ADHD
ADHD
ADHD
T2
T3
T1
27
(No Transcript)
28
ACE Model of Bivariate Association Between
Smoking Initiation and Nicotine Dependence
(Kendler et al., 2000)
Ai
Ci
Ei
.15
.78
.07
Initiation
.77
Dependence
.13
.20
.08
Ad
Cd
Ed
Coefficients are variance proportions except for
initiation-dependence
29
(No Transcript)
30
(No Transcript)
31
Reward Craving (positive affective situations or
suboptimal arousal states)
Dopaminergic Dysregulation Reward Seeking (high
behavioral activation, sensitivity to positive
reinforcement)
Gabaergic/glutaminergic Dysregulation Stress
Reactivity (hyperarousability, sensitivity to
aversive stimuli and punishment)
Relief Craving (negative affect situations and
withdrawal symptoms)
Serotonergic Dysregulation Disinhibition (hyperaro
usability, sensitivity to aversive stimuli and
punishment)
Obsessive Craving (not cue-elicited compulsion
loss of control)
32
The DRD4 VNTR Polymorphism Influences Reactivity
to Smoking Cues Kent E. Hutchison a, Heather
LaChance a, Raymond Niaura b, Angela D. Bryan a,
and Andrew Smolen c University of Colorado -
Boulder,a Centers for Behavioral and Preventive
Medicine, Brown Medical School and The Miriam
Hospital,b Institute for Behavioral Genetics at
the University of Colorado Boulder c
33
Table 1. DRD4 VNTR allele and genotype
frequencies.
34
Genotypes 2/2 4 5.88 2/4 8 11.76
2/7 1 1.47 3/3 2 2.94 3/4 3 4.41
3/7 2 2.94 4/4 30 44.12
4/5 1 1.47 4/7 16 23.53
7/8 1 1.47 Total 68 100
Genotype Classification L 20 29.41
S 48 70.59 Total 68 100
35
Table 2. Pretest Differences in DRD4 S versus
DRD4 L
36
(No Transcript)
37
(No Transcript)
38
(No Transcript)
39
(No Transcript)
40
(No Transcript)