close

Вход

Забыли?

вход по аккаунту

?

Association of the phosphatase and tensin homolog gene (PTEN) with smoking initiation and nicotine dependence.

код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 141B:10 – 14 (2006)
Association of the Phosphatase and Tensin Homolog Gene
(PTEN) With Smoking Initiation and Nicotine Dependence
Lan Zhang,1,2 Kenneth S. Kendler,1 and Xiangning Chen1*
1
Department of Psychiatry, Virginia Institute of Psychiatric and Behavioral Genetics, Virginia Commonwealth University,
Richmond, Virginia
2
Department of Psychiatry, West China Hospital, Sichuan University, Chengdu, China
Since PTEN (phosphatase and tensin homolog)
has elevated expression in rat brain (amygdala)
after chronic administration of nicotine and the
PTEN gene is located in the vicinity of the
chromosome 10q23 linkage peak in a genome-scan
study of nicotine dependence, PTEN seems a
plausible candidate gene for smoking behavior.
To test this hypothesis, we use a three-group casecontrol design and genotype five SNPs in the
PTEN gene. We compare allele and genotype
frequencies between the smokers and nonsmokers and between the low nicotine dependent
and high nicotine dependent subjects. Three SNPs
in the PTEN gene are significantly associated
with smoking initiation (rs1234221, P ¼ 0.0311;
rs1234213, P ¼ 0.0002; and rs2735343, P ¼ 0.0028).
Rs1234213 also shows association with nicotine
dependence (P ¼ 0.0278). Haplotype analyses
indicate that a major haplotype, 1-1-2-2-1 for
rs1234221-rs2299939-rs1234213-rs2735343-rs70184,
is associated with smoking initiation. A minor
haplotype (about 3%), 1-2-2-2-1 for the same five
SNPs, is observed only in the high nicotine
dependence group. These results suggest that
the PTEN gene may be involved in the etiology
of both smoking initiation and nicotine dependence.
ß 2005 Wiley-Liss, Inc.
KEY WORDS: PTEN; smoking initiation; nicotine dependence; association
study
INTRODUCTION
Tobacco smoking is a complex and addictive behavior.
Earlier epidemiologic and genetic studies have established
that both environmental and genetic factors play a significant
role in smoking [True et al., 1997; Kendler et al., 1999; Li et al.,
2003; Munafo et al., 2004]. Other studies indicate that the
course from the start of smoking to becoming addicted is an
evolving process that includes at least two major stages:
smoking initiation (SI) and progression to nicotine dependence
[U.S. Department of Health and Human Services, 1989;
Kendler et al., 1999]. Genetic factors play important roles in
both stages [Sullivan and Kendler, 1999]. These findings have
lead to the search for genes predisposing to tobacco smoking
and nicotine dependence. Despite some successful results
[Tyndale, 2003; Feng et al., 2004], however, the search in
general has not been very productive. In addition to other
factors such as sample size and power, lack of robust strategies
to identify biologically plausible candidate genes may be a
contributing factor. We recently have explored a strategy that
uses microarray profiling as a screening tool to identify
candidates for association study [Chen et al., 2004]. This
report is a continuation of our efforts to test more candidate
genes identified through microarray studies and other
approaches.
The PTEN (phosphatase and tensin homolog) gene is
involved in inositol (1,4,5)-trisphosphate (Ins(1,4,5)P3) turnover as well as intracellular calcium homeostasis [Berridge,
2005]. PTEN negatively regulates intracellular levels of
Ins(1,4,5)P3 in cells and also functions as a tumor suppressor
by negatively regulating Akt (also known as protein kinase B,
PKB) signaling pathway [Roth, 2004; Sansal and Sellers, 2004;
Kim et al., 2005]. In a microarray study, the expression of the
PTEN gene was elevated in the amygdala of rat brain [Konu
et al., 2001]. The PTEN gene is located at 10q23, a region
implicated in a linkage study of nicotine dependence [Straub
et al., 1999]; the peak marker D10S2469 is about16 million
basepairs telomeric to the PTEN gene. Another linkage study
with illegal drugs also produced a linkage peak in the same
region [Uhl et al., 2001]. Given the fact that both smoking
initiation (SI) and nicotine dependence (ND) are complex
traits, relatively low penetrance and a small effect are expected
of individual genes, the distance between the PTEN gene and
the linkage peak is well within the confidence interval of the
linkage region [Roberts et al., 1999]. Combining the information of its elevated expression upon nicotine exposure and
chromosomal location under a linkage peak, we hypothesize
that PTEN gene may be involved in tobacco smoking and ND.
Based on this rationale, we conduct this study.
MATERIALS AND METHODS
Subjects
Grant sponsor: NIH; Grant numbers: MH-40828, MH/AA/DA49492, AA-09095; Grant sponsor: NIDA INVEST International
Fellowship; Grant sponsor: Virginia Tobacco Settlement Foundation; Grant number: 8520012.
*Correspondence to: Xiangning Chen, Virginia Institute for
Psychiatric and Behavioral Genetics and Department of Psychiatry, Virginia Commonwealth University, 800 Leigh Street, Suite
1-110, Richmond, VA 23298. E-mail: xchen@vcu.edu
Received 1 February 2005; Accepted 18 July 2005
DOI 10.1002/ajmg.b.30240
ß 2005 Wiley-Liss, Inc.
A total of 688 subjects used in this study were selected
from two large, population-based twin studies [Kendler and
Prescott, 1999; Kendler et al., 1999]. We randomly chose one
subject from a twin pair who were all of European ancestry and
unrelated. Smoking data collected included smoking history,
the Fagerstrom tolerance questionnaire (FTQ) reported for
the time of maximal tobacco consumption [Fagerstrom, 1978]
and the severity of withdrawal symptoms. The FTQ was used
as the phenotype to measure the degree of ND. Based on their
smoking history and the FTQ scores, the subjects were divided
into three groups: lifetime nonsmokers (NS) who reported
0.741
0.486
0.671
0.045
0.829
11
7
39
23
31
82
53
112
113
100
124
153
70
72
75
0.093
0.934
0.621
0.174
0.054
18
5
22
16
49
68
50
90
90
88
122
145
77
74
71
0.143
0.278
0.886
0.872
0.357
26
7
20
16
54
87
51
92
91
108
119
173
115
114
72
—
40671
32171
16108
21316
A/C, A
C/A, C
G/A, G
G/C, G
T/C, T
rs1234221
rs2299939
rs1234213
rs2735343
rs701848
22
P-value of
HWE test
11
12
22
P-value of
HWE test
11
12
High-ND
Low-ND
NS
22
12
11
Distance between
SNPs (bp)
Polymorphism,
major allele
Marker
name
Data Analysis
The genotypes were checked for deviation from Hardy–
Weinberg equilibrium. To examine SI, we compared the
nonsmokers with both low-ND and high-ND smokers. For
ND, we compared the Low-ND group with the High-ND group.
We used w2 tests to compare the allele and genotype frequencies
for each of the five markers typed for the sample. Linkage
disequilibrium (LD), as assessed by D0 and r2, was calculated by
the FAMHAP software [Becker and Knapp, 2004] and the
haplotype blocks were estimated using the confidence-interval
Numbers of genotypes in the three subject groups
SNP Selection and Genotyping
The PTEN gene is about 102 kb in length. Five haplotypetagged SNPs spanning the gene were selected using the
software SNP Browser designed by Applied Biosystems
Incorporated (ABI, Foster City, CA). The haplotype tagged
SNPs were selected based on Caucasian genotype data. None of
the five SNPs were in exons and no functions of these SNPs
were known. They were selected solely on the basis that they
tagged and differentiated major haplotypes of the PTEN gene.
SNPs were genotyped by the 50 nuclease cleavage assay (also
called TaqMan method) [Livak, 1999]. Reactions were performed in 384-well plates with 5 ml reaction volume containing
0.25 ml of 20X Assays-on-DemandTM SNP assay mix, 2.5 ml of
TaqMan universal PCR master mix and 5 ng of genomic DNA.
The conditions for PCRs were initial denaturizing at 958C for
10 min, followed by 40 cycles of 928C for 15 sec and 558C for
1 min. After the reaction, fluorescence intensities for reporter
1 (VIC, exercitation ¼ 520 10 nm, emission ¼ 550 10 nm)
and reporter 2 (FAM, exercitation ¼ 490 10 nm, emission ¼
510 10 nm) were read by the Analyst fluorescence plate
reader (LJL Biosytems, Sunnyvale, CA). Genotypes were
scored by a Euclidian clustering algorithm developed in our
laboratory [van den Oord et al., 2003].
TABLE I. Characteristics of the Five Genotyped SNPs
never having smoked an entire cigarette in their lives; regular
smokers with low nicotine dependence (low-ND) who smoked
regularly (five cigarettes per week) for at least 5 years but
whose FTQ scores were 0–2; and regular smokers with high
nicotine dependence (high-ND) who smoked regularly for at
least 5 years with FTQ scores of 7–11 during their lifetime
period of maximum use. In this study, we intended to test the
genetic factors separately for SI and ND. To accomplish this
goal, we used the 3-group study design. To access genetic
factors involved in SI, we compared the nonsmokers with
regular smokers, which includes both the Low- and High-ND
groups. To identify factors involved in ND, we compared the
Low-ND and High-ND groups. In classifying the subjects, we
used a stringent definition for low-ND smokers. We realized
that this definition excluded a fraction of smokers (some of
whom might be called light social smokers or ‘‘chippers’’). For
the two population samples used in this study, this very light
smoker group who did not meet the inclusion criteria for
current study accounted for about 23–25% of the total samples.
We did not include these subjects because we were not
confident that they all had a low liability to ND due to
insufficient nicotine exposure. For this reason, our test for ND
was more stringent than most other two-group case-control
studies. The sample in this study included 244 nonsmokers,
215 low-ND smokers, and 229 high-ND smokers. All subjects
provided informed consent and used standard cytology brushes
to obtain buccal epithelial cells for DNA extraction. The
method for DNA extraction from the cytology brushes was
described previously [Straub et al., 1999]. The population
stratification was evaluated by typing 16 unlinked microsatellite makers and no significant stratification was found
[Sullivan et al., 2001b].
P-value of
HWE test
The PTEN Gene and Smoking
11
12
Zhang et al.
TABLE II. Allelic and Genotypic Associations Between the Genotyped SNPs and SI and ND
Genotype
Allele
SI
Marker
name
rs1234221
rs2299939
rs1234213
rs2735343
rs701848
ND
SI
ND
w2
P
w2
P
w2
P
w2
P
4.82
0.67
14.44
11.28
1.49
0.0898
0.7165
0.0007
0.0036
0.4749
2.82
0.23
5.00
1.88
4.92
0.2437
0.8929
0.0821
0.3908
0.0856
4.65
0.40
13.85
8.93
2.07
0.0311
0.5279
0.0002
0.0028
0.1503
0.12
0.08
4.84
1.57
2.47
0.7252
0.7720
0.0278
0.2105
0.1161
method implemented in the HAPLOVIEW program [Gabriel
et al., 2002; Barrett et al., 2005]. FAMHAP software was also
used for haplotype analyses. P-values for haplotype associations were obtained by simulations of the FAMHAP program.
RESULTS
Six hundred eighty-eight subjects were genotyped for five
SNPs in the region of the PTEN gene. Of these SNPs,
rs2299939, rs1234213, and rs2735343 were within the PTEN
gene, rs1234221 and rs701848 were located within 10 kb
distance centromeric and telomeric to the PTEN gene. Of the
five typed SNPs, one (rs2735343) slightly deviated from HWE
(w2 ¼ 4.98, P ¼ 0.026) when all subjects were combined. To
examine if the deviation was caused by genotyping errors, we
computed the deviations (P-values) for the three groups
separately. As shown in Table I, the deviation was restricted
to high-ND smokers only. Two more markers, rs1234221 and
rs701848, showed marginal deviations in the Low-ND group.
In contrast, none of the five typed SNPs showed significant
deviations in the nonsmokers (controls). This information, by
itself, was supportive of the association between the PTEN
gene and tobacco smoking, because modest deviations in HWE
in the affected subjects can be due to association [Hoh et al.,
2001]. The average scoring rate for the five SNPs was 93%
(from 89 to 95%).
To investigate the associations for SI and ND, we compared
the genotype and allele frequencies amongst the nonsmokers,
the low-ND and high-ND smokers (Table II). Of the five SNPs
typed, three of them (rs1234221, rs1234213, and rs2735343)
showed significant differences in allele frequencies between
the nonsmokers and regular smokers (P ¼ 0.0311, 0.0002, and
0.0028 respectively). Genotypically, rs1234213 and rs2735343
also showed significant differences between the nonsmokers
and regular smokers (P ¼ 0.0007 and 0.0036). Rs1234221
showed a trend (P ¼ 0.0898). When the low-ND and high-ND
smokers were compared, rs1234213 showed significant allelic
association, where the high-ND smokers had a higher
frequency (43% vs. 34.5%) for the minor allele (allele A).
To understand the haplotype structure of the PTEN gene, we
calculated pairwise LDs (D0 and r2) for the five typed SNPs
(Table III). There were substantial LD between these SNPs,
especially between rs1234212 and rs2735343, where the LD
was very strong (D0 ¼ 0.95, r2 ¼ 0.90). When analyzed by the
HAPLOVIEW program, the five SNPs were partitioned into
three LD blocks by the confidence interval algorithms.
Rs1234221 and rs2299939 formed the first block, rs1234213
and rs2735343 formed the second block and rs701848 stood
alone. This was slightly different from the structure of the
Caucasian sample typed by the HapMap project where
rs2299939, rs1234213, and rs2735343 were all in the same
LD block and rs1234221 was located in the inter-block region
(rs701948 was not typed by the HapMap project, but by its
chromosomal position, it belonged to the same block as
rs2299939, rs1234213, and rs2735343).
In haplotype association analyses, we tested 2- , 3- and 4marker haplotypes for both SI and ND (Table IV). In 2-marker
analyses, all combinations, except 1-2, 1-5, and 2-5, reached
global significance for SI. In 3- and 4-marker analyses, all
haplotypes that carried the minor alleles for both rs1234213
and rs2735343 were significant despite some combinations
were not globally significant. Combining the risk haplotype
information observed from these 2-, 3- and 4-marker haplotype
tests, we found that a major haplotype, 1-1-2-2-1 for the five
tested markers, was consistently overrepresented in smokers
compared to nonsmokers. This was confirmed by direct testing
of 5-marker haplotypes where haplotype 1-1-2-2-1 had a Pvalue of 0.0221 while the global P-value was not significant
(P ¼ 0.1236) (data not shown). The frequency of this haplotype
was about 7–9% higher in the smokers than the nonsmokers
regardless how many markers were used for the analyses
(Table IV), giving a relatively constant odds ratio of 1.3.
These results were consistent with the haplotype structure
observed in the gene, where the tight LD between rs1234213
and rs2735343 constituted the core of this haplotype. It was the
minor alleles of these two markers that separated this risk
haplotype from other haplotypes. This was also consistent with
the single marker association results where rs1234213 and
rs2735343 produced the most significant associations.
For ND, many marker combinations did not yield significant
results. In two 2-marker combinations, that is, 2-3 and 2-4, a
minor haplotype (about 3–4%) was detected only in the HighND group. These results were consistent with multi-marker
analyses (combinations 1-2-3, 2-3-4, and 2-3-4-5) despite that
TABLE III. Pairwise LDs of the SNPs in the PTEN Gene*
rs1234221
rs1234221
rs2299939
rs1234213
rs2735343
rs701848
0
0.96
0.68
0.64
0.75
2
rs2299939
rs1234213
rs2735343
rs701848
0.06
0.09
0.08
0.08
0.06
0.90
0.25
0.17
0.26
0.24
0.83
0.71
0.82
*D , below the diagonal; r ,above the diagonal.
0.95
0.76
0.74
The PTEN Gene and Smoking
13
TABLE IV. Haplotype Associations Between the PTEN Gene and SI and ND
Marker
combination*
Global
P-value
1-3
1-4
2-3
3-4
3-5
1-2-3
1-3-4
2-3-4
3-4-5
1-3-5
1-4-5
1-2-3-4
2-3-4-5
0.0053
0.0289
0.0162
0.0100
0.0078
0.0158
0.0231
0.0526
0.1323
0.0431
0.2026
0.0308
0.0647
2-3
2-4
3-4
3-5
1-2-3
2-3-4
2-3-4-5
0.0348
0.0369
0.2183
0.0504
0.1022
0.1241
0.2386
Risk
haplotype
Haplotype frequency
(case:control)
Smoking initiation
1-2
0.36:0.27
1-2
0.33:0.25
1-2
0.38:0.29
2-2
0.38:0.29
2-1
0.35:0.26
1-1-2
0.35:0.27
1-2-2
0.35:0.27
1-2-2
0.37:0.29
2-2-1
0.35:0.26
1-2-1
0.32:0.24
1-2-1
0.30:0.23
1-1-2-2
0.34:0.27
1-2-2-1
0.34:0.26
Nicotine dependence
2-2
0.03:0.00
2-2
0.04:0.00
2-2
0.41:0.35
2-1
0.40:0.31
1-2-2
0.03:0.00
2-2-2
0.03:0.00
2-2-2-1
0.02:0.00
Odds ratio
Haplotype
P-value
1.33
1.33
1.31
1.32
1.38
1.27
1.29
1.27
1.34
1.34
1.31
1.25
1.28
0.0017
0.0032
0.0011
0.0007
0.0006
0.0057
0.0061
0.0042
0.0021
0.0037
0.0071
0.0167
0.0105
N/A
N/A
1.19
1.30
N/A
N/A
N/A
0.0445
0.0195
0.0369
0.0058
0.0425
0.0324
0.0360
*Key to marker combinations: 1, rs1234221; 2, rs2299939; 3, rs1234213; 4, rs2735343; 5, rs701848.
the global tests did not reach significance (Table IV). When all
five markers were included, this minor haplotype observed
only in the High-ND group was 1-2-2-2-1. Rs2299939 was the
marker that differentiated the 1-1-2-2-1 haplotype, which was
overrepresented in regular smokers, from the 1-2-2-2-1
haplotype, which was only observed in high-ND smokers.
DISCUSSION
In this study, we use a three-group case-control design to
investigate if the PTEN gene is involved in smoking behaviors,
that is, smoking initiation and nicotine dependence. We have
genotyped five SNPs in the PTEN gene and compared the
allelic and genotypic frequencies amongst the nonsmokers,
low-ND and high-ND smokers. In single marker analyses, we
find that three SNPs (rs1234221, rs1234213, and rs2735343)
are associated with SI and one SNP (rs1234213) is associated
with ND. Two-, 3- and 4-marker haplotype analyses indicate
that there is a major haplotype (1-1-2-2-1) over-represented in
the smokers and there is a minor haplotype (1-2-2-2-1)
observed only in the high-ND smokers. These results indicate
that haplotype 1-1-2-2-1 might elevate the risk to smoking and
haplotype 1-2-2-2-1 correlates with high nicotine dependence.
Twin studies [Kendler et al., 1999; Maes et al., 2004] suggest
that the genetic factors impacting on smoking initiation and
nicotine dependence are correlated, albeit not identical. It is
interesting that we find different haplotypes in the PTEN gene
that are specifically associated with smoking initiation and
nicotine dependence.
There are several factors that can potentially cause false
positive results in association studies. The most common ones
include population stratification, lack of priori knowledge of
the candidates and sample size and power. The subjects used in
this study are of European descent and not related. We have
evaluated potential stratification by typing 16 unlinked
microsatellite markers and no significant evidence of population stratification is found [Sullivan et al., 2001a]. This reduces
the probability that results obtained in this study are caused by
population stratification. The PTEN gene is not randomly
selected for this study. It has been shown to be upregulated in
the amygdala of rat brain after chronic exposure of nicotine.
This upregulation is confirmed by real-time RT-PCR. Functionally, PTEN is involved in the regulation of inositol triphosphatase, a secondary messenger that regulates many cellular
processes, including the Caþþ signal pathway that is involved
in cellular responses to external stimuli in many different cell
types [Berridge, 2005]. In addition, PTEN is located under a
linkage peak found by previous genome scan studies [Straub
et al., 1999; Uhl et al., 2001]. Taking all together, this
information suggests that PTEN is likely to have a functional
role in cellular response to nicotine and may contribute to
tobacco smoking in humans. The priori knowledge increases
the likelihood that findings in this study are truly positive.
Furthermore, our relatively large sample size gives us reasonable power to detect genes with modest effects. In conclusion,
our results indicate that PTEN gene is associated with
cigarette smoking and possibly involved in both the initiation
of smoking and progression to nicotine dependence. However,
given our poor understanding of the pathophysiology of
smoking and nicotine dependence, further replications are
necessary before definitive conclusions can be made.
ACKNOWLEDGMENTS
This study was supported by Virginia Tobacco Settlement
Foundation through the Virginia Youth Tobacco Project to
Virginia Commonwealth University. We thank Dr. Linda
Corey for assistance with the ascertainment of twins from
the Virginia Twin Registry, now part of the Mid-Atlantic Twin
Registry (MATR), currently directed by Dr. Judy Silberg. The
MATR has received support from the National Institutes of
Health, the Carman Trust and the WM Keck, John Templeton
and Robert Wood Johnson Foundations.
REFERENCES
Barrett JC, Fry B, Maller J, Daly MJ. 2005. Haploview: Analysis and
visualization of LD and haplotype maps. Bioinformatics 21:263–265.
Becker T, Knapp M. 2004. A powerful strategy to account for multiple testing
in the context of haplotype analysis. Am J Hum Genet 75:561–570.
Berridge MJ. 2005. Unlocking the secrets of cell signaling. Annu Rev Physiol
67:1–21.
14
Zhang et al.
Chen X, Wu B, Kendler KS. 2004. Association study of the Epac gene and
tobacco smoking and nicotine dependence. Am J Med Genet 129B:
116–119.
Roberts SB, MacLean CJ, Neale MC, Eaves LJ, Kendler KS. 1999.
Replication of linkage studies of complex traits: An examination of
variation in location estimates. Am J Hum Genet 65:876–884.
Fagerstrom KO. 1978. Measuring degree of physical dependence to tobacco
smoking with reference to individualization of treatment. Addict Behav
3:235–241.
Roth MG. 2004. Phosphoinositides in constitutive membrane traffic. Physiol
Rev 84:699–730.
Feng Y, Niu T, Xing H, Xu X, Chen C, Peng S, Wang L, Laird N, Xu X. 2004. A
common haplotype of the nicotine acetylcholine receptor alpha 4 subunit
gene is associated with vulnerability to nicotine addiction in men. Am J
Hum Genet 75:112–121.
Gabriel SB, et al. 2002. The structure of haplotype blocks in the human
genome. Science 296:2225–2229.
Hoh J, Wille A, Ott J. 2001. Trimming, weighting, and grouping SNPs in
human case-control association studies. Genome Res 11:2115–2119.
Sansal I, Sellers WR. 2004. The biology and clinical relevance of the PTEN
tumor suppressor pathway. J Clin Oncol 22:2954–2963.
Straub RE, et al. 1999. Susceptibility genes for nicotine dependence: A
genome scan and followup in an independent sample suggest that
regions on chromosomes 2, 4, 10, 16, 17 and 18 merit further study. Mol
Psychiatry 4:129–144.
Sullivan PF, Kendler KS. 1999. The genetic epidemiology of smoking.
Nicotine Tob Res 1(Suppl 2):S51–S57.
Kendler KS, Prescott CA. 1999. A population-based twin study of lifetime
major depression in men and women. Arch Gen Psychiatry 56:39–44.
Sullivan PF, Jiang Y, Neale MC, Kendler KS, Straub RE. 2001a. Association
of the tryptophan hydroxylase gene with smoking initiation but not
progression to nicotine dependence. Am J Med Genet B 105:479–484.
Kendler KS, Neale MC, Sullivan P, Corey LA, Gardner CO, Prescott CA.
1999. A population-based twin study in women of smoking initiation and
nicotine dependence. Psychol Med 29:299–308.
Sullivan PF, et al. 2001b. An association study of DRD5 with smoking
initiation and progression to nicotine dependence. Am J Med Genet B
105:259–265.
Kim D, et al. 2005. AKT/PKB signaling mechanisms in cancer and chemoresistance. Front Biosci 10:975–984.
True WR, Heath AC, Scherrer JF, Waterman B, Goldberg J, Lin N, Eisen SA,
Lyons MJ, Tsuang MT. 1997. Genetic and environmental contributions
to smoking. Addiction 92:1277–1287.
Konu O, et al. 2001. Region-specific transcriptional response to chronic
nicotine in rat brain. Brain Res 909:194–203.
Li MD, Cheng R, Ma JZ, Swan GE. 2003. A meta-analysis of estimated
genetic and environmental effects on smoking behavior in male and
female adult twins. Addiction 98:23–31.
Tyndale RF. 2003. Genetics of alcohol and tobacco use in humans. Ann Med
35:94–121.
Livak KJ. 1999. Allelic discrimination using fluorogenic probes and the 50
nuclease assay. Genet Anal 14:143–149.
U.S. Department of Health and Human Services. 1989. Reducing the health
consequences of smoking: 25 years of progress. Rockville, MD: Office on
Smoking and Health, Center for Chronic Disease Prevention and Health
Promotion, Centers for Disease Control, Public Health Sevice, U.S.
Department of Health and Human Services.
Maes HH, Sullivan PF, Bulik CM, Neale MC, Prescott CA, Eaves LJ,
Kendler KS. 2004. A twin study of genetic and environmental influences
on tobacco initiation, regular tobacco use and nicotine dependence.
Psychol Med 34:1251–1261.
Uhl GR, Liu QR, Walther D, Hess J, Naiman D. 2001. Polysubstance abusevulnerability genes: Genome scans for association, using 1,004 subjects
and 1,494 single-nucleotide polymorphisms. Am J Hum Genet 69: 1290–
1300.
Munafo M, Clark T, Johnstone E, Murphy M, Walton R. 2004. The genetic
basis for smoking behavior: A systematic review and meta-analysis.
Nicotine Tob Res 6:583–597.
van den Oord EJ, Jiang Y, Riley BP, Kendler KS, Chen X. 2003. FP-TDI SNP
scoring by manual and statistical procedures: A study of error rates and
types. Biotechniques 34:610–620, 622.
Документ
Категория
Без категории
Просмотров
1
Размер файла
65 Кб
Теги
homology, pten, associations, smoking, nicotine, tensin, dependence, genes, phosphatase, initiative
1/--страниц
Пожаловаться на содержимое документа