Neuronal nAchR genes in smoking behavior and addiction Público
Wiste, Anna Katrina (2009)
Abstract
The nicotinic acetylcholine receptor subunit gene cluster on
chromosome 15
containing CHRNA5, CHRNA3 and CHRNB4 has been highlighted in
several
association studies of genetic influences on smoking and
smoking-related diseases. We
reported genome-wide significant association of the synonymous SNP,
rs1051730, with
smoking quantity, and also demonstrated that the T allele of this
variant carried an
increased risk of nicotine dependence, lung cancer and peripheral
arterial disease.
Given the high rate of smoking among individuals with other
substance
dependence disorders, we sought to determine whether this variant
also increased risk for
dependence on other substances. Subjects met DSM criteria for
dependence for at least
one substance of abuse, including alcohol, amphetamine, cannabis,
opiates, and
sedatives/anxiolytics. Smoking quantity information was available
from questionnaire
data for a subset of subjects. Among alcohol dependent subjects the
variant had the same
effect on smoking quantity as observed in the general
population.
To characterize the region, the role of variants within the region
in regulation
of gene expression was explored. Blood and adipose tissue from a
large sample of
subjects was used to test for association of the variant to
expression of CHRNA5. Several
correlated variants within the region show significant association
to expression of
CHRNA5.
The association with smoking and smoking-related disease reported
in our
study and others has been observed in genome-wide association
studies. In most cases,
association signals detected in genome-wide association studies are
expected to be
indirect, occurring through linkage disequilibrium with a
functional variant. To identify
the most likely functional variant responsible for the association
signal we have
performed sequencing in the gene cluster in 3 samples: nicotine
dependence, lung cancer,
and low quantity smokers. Among common variants in the cluster no
variants were
identified with stronger association than rs1051730. A functional
SNP in CHRNA5,
rs16969968, is in perfect LD with rs1051730 in Iceland, and it is
the only common
functional SNP in the cluster. Based upon these factors, rs16969968
is currently the
variant most likely to be responsible for the association signals
observed in this cluster to
smoking behavior and smoking-related diseases.
Table of Contents
Table of Contents
General
Introduction…………………………………………………………………1
Chapter 1:
Introduction……………..……………………………………………....2
A. Genome-wide Association Studies and Their Impact on Genetics
of
Complex
Disease......................................................................................................2
B. Definition of
Phenotypes.....................................................................................5
C. Genetic Basis of Smoking Behavior and Nicotine
Dependence........................12
D. Nicotinic acetylcholine receptors - structure and role in
nicotine
Dependence.............................................................................................................12
E. Identification of Risk Variant in CHRNA5/CHRNA3/CHRNB4
gene
cluster......................................................................................................................14
F. Additional findings on the CHRNA5/CHRNA3/CHRNB4 gene
cluster
variant......................................................................................................................17
G. Previous Characterizations of the
Region...........................................................18
H. Functional Importance of Genes in the
Cluster..................................................19
I.
Objectives.............................................................................................................20
Chapter 2: Association of Smoking Quantity with a
CHRNA5/CHRNA3/CHRNB4
variant in Substance Dependence, but no Association of Variants
within the Cluster
to Substance Dependence itself.
A.
Abstract………………………………………………………………………...23
B.
Introduction………………………………………………………………….....24
C. Materials and
Methods...……………………………………………………….25
D.
Results………………………………………………………………………….28
E.
Discussion……………………………………………………………………..29
Chapter 3: Characterization of the
CHRNA5/CHRNA3/CHRNB4
nicotinic
acetylcholine receptor gene cluster in nicotine dependence and lung
cancer
A.
Abstract………………………………………………………………………...39
B.
Introduction…………………………………………………………………….40
C.
Results………………………………………………………………………….42
D.
Discussion……………………………………………………………………...48
E. Materials and
Methods……………………………………………………...….51
Chapter 4
Discussion………………………………………………………..………..74
A. Summary of
Results…………………………………………………………….75
B. Other substances of
abuse....................................................................................76
C. Sequencing and Expression
Analysis...................................................................77
D.
Conclusions……………………………………………………………………..80
Chapter 5:
References………………………………………………………………..83
Figures and Tables
Figure 1.1 - DSM-IV Criteria for Substance Dependence.......................................10
Figure 1.2 - Fagerström Test of Nicotine Dependence (FTND)…………………...11
Table 2.1 - Demographic Description………………………………………………32
Table 2.2 - Association of Variants in the LD block with Alcohol Dependence....33
Table 2.3 - Association of Variants Tested to Other Substance Dependence
Diagnoses………………………………………………………………..34
Table 2.4 - Regression Analysis of rs1051730 and Smoking Quantity…………...35
Table 2.5.A - Alcohol and Amphetamine Dependence……………………………36
Table 2.5.B - Cannabis, Opioid and Sedative, Anxiolytic and Hypnotic (SAH)
Dependence……………………………………………………………37
Figure 3.1 - Illustration of the risk for nicotine dependence observed for
rs1051730 (1) and rs578776 (2) based on the comparison of 2161 nicotine
dependent individuals and 865 low quantity smokers..............................................57
Figure 3.2 - The short allele of rs3841324 is associated with increased
expression of CHRNA5 RNA in blood and subcutaneous adipose tissue...............58
Table 3.1 - Comparison of frequency of markers with minor allele frequency
> 1% in Lung Cancer (LC), Nicotine Dependence (ND) and
Low
Quantity Smokers
(LQS)………….........……………………………….59
Table 3.2 - Equivalence classes for SNPs with minor allele
frequency greater
than
5%.......................................................................................................61
Table 3.3 - Association Results for Equivalences Classes in
Larger Samples…....62
Table 3.4 - Association Results for Insertion/Deletions and
Microsatellites….…..63
Table 3.5 - Association analysis of CHRNA5 expression with variants
in the
LD
block………………………………………………………………….64
Table 3.6 - Demographics: Sequencing
Cohort…………………………………….65
Table 3.7 - Descriptive information on all variants from
sequencing…………….66
Table 3.8 - All variants with frequency less than
1%...............................................69
Table 3.9 - Demographics for cohorts used in analyses including
additional
genotyping……………………………………………………………….70
Table 3.10 - Full list of sequencing primers
used………………………………….71
Table 3.11 - Build 36 positions for regions
sequenced…………………………….74
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