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Pleiotropic effect of the TPH A779C polymorphism on nicotine dependence and personality.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 134B:20 – 24 (2005)
Pleiotropic Effect of the TPH A779C Polymorphism
on Nicotine Dependence and Personality
M. Reuter* and J. Hennig
Department of Psychology, Center of Psychobiology and Behavioral Medicine, University of Giessen, Giessen, Germany
Recent studies from molecular genetics have
suggested an association between the tryptophan
hydroxylase 1 (TPH1) gene and nicotine addiction indicating a dysfunction of the serotonergic
(5-HT) system in smoking behavior. In a sample of
252 healthy subjects, a significant association
between variations observed in nicotine dependence and the heterozygous AC-genotype of the
TPH A779C polymorphism could be demonstrated. Moreover, the heterozygous genotype was
significantly associated with a personality trait
of neurotic aggression (indirect hostility, negativism), as measured by the Buss–Durkee-HostilityInventory (BDHI). The positive heterosis effects
with respect to nicotine addiction and personality
support the idea that the TPH1 gene exerts
pleiotropic effects.
ß 2005 Wiley-Liss, Inc.
KEY WORDS: TPH1 A779C polymorphism; 5-HT;
nicotine addiction; personality;
pleiotropic effect
INTRODUCTION
Studies from behavioral genetics reveal the high heritability
of smoking behavior, ranging from 47% to 76% [Heath et al.,
1995; Hughes et al., 1997], which is at least as high as the
heritability of alcohol dependence [Hughes et al., 1997].
Candidate genes that contribute to the phenotype of nicotine
dependence were polymorphisms in cytochrome P450 genes,
which are involved in nicotine metabolism, and genes relevant
for the metabolism of dopamine (DA) because DA was assumed
to be the final common pathway of reward (for a review see
Spanagel and Weiss, 1999). Several authors also reported
associations between polymorphisms in genes of the serotonergic system (5-HT system) and smoking behavior. The 5-HT
system is involved in many physiological and psychological
processes including sleep, appetite, mood, aggression, and
sexual behavior. The link to nicotine dependence comes from
evidence that nicotine increases 5-HT in the central nervous
system and that central 5-HT levels decrease during nicotine
withdrawal [Ribeiro et al., 1993; Mihailescu et al., 2002]. Based
on these findings, the hypothesis has put forward that mood
and appetite disturbances during nicotine withdrawal are
mediated through a reduced activity of the 5-HT system
[Ribeiro et al., 1993].
*Correspondence to: Dr. M. Reuter, Department of Psychology,
Justus-Liebig-University of Giessen, Otto-Behaghel-Str. 10F,
D-35394 Giessen, Germany.
E-mail: [email protected]
Received 2 August 2004; Accepted 20 October 2004
DOI 10.1002/ajmg.b.30153
ß 2005 Wiley-Liss, Inc.
Lerman et al. [2001] reported an association between the
A779C single nucleotide polymorphism (SNP) of the tryptophan hydroxylase 1 (TPH1) gene and smoking behavior.
However, only the age of smoking initiation differed significantly between groups defined by genotypes, with lowest age at
smoking initiation in carriers of the AA genotype and highest
age in carriers of the CC genotype. Other smoking related
variables were not linked to the TPH1 polymorphism, including (a) the degree of nicotine dependence measured by the
Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton
et al., 1991], (b) smoking status, (c) quitting history, and (d)
current smoking rate. In another study, Sullivan et al. [2001]
reported associations for the A779C SNP and for another
marker in the seventh intron of the TPH gene [i.e., the C218A
SNP] and smoking initiation but not progression to nicotine
dependence. In order to evaluate an association with smoking
initiation, frequencies of genotypes, alleles, and haplotypes of
the two loci of the TPH1 gene, that could be demonstrated to be
in strong linkage disequilibrium [Nielsen et al., 1997; Kunugi
et al., 1999; Marshall et al., 1999], were compared between
lifetime nonsmokers and smokers (regular smokers with low
and high scores on the Fagerstrom Tolerance Questionnaire
(FTQ) [Fagerstrom, 1978]. A possible association between the
TPH1 markers and the progression to nicotine dependence
was tested by comparing frequencies of genotypes, alleles, and
haplotypes between smokers with low or high FTQ scores.
With respect to smoking initiation, there were highly significant differences in genotype, allele, and haplotype frequencies between lifetime nonsmokers and regular smokers. The
A-allele and the A-haplotype were more prevalent in smokers
than in nonsmokers. Although, the findings of Sullivan et al.
[2001] and Lerman et al. [2001] did not yield identical results,
they nonetheless revealed both a significant association
between the A-allele of the C779A polymorphism and variables
relevant for smoking behavior. Because both TPH1 markers
(C218A and C779A) are located in a noncoding region and
because no exon skipping or alternative splicing have been
reported, it is assumed that these polymorphisms are not
etiological mutations but may be in linkage disequilibrium
with an as yet unidentified polymorphism in the TPH gene
[Han et al., 1999; Rotondo et al., 1999]. Recently, Walther et al.
[2003] identified a second TPH isoform-referred to as TPH2—
in mice which is predominatly expressed in the brain stem,
while the classical TPH gene—now called TPH1—is expressed in the gut, pineal gland, spleen, and thymus. The authors
also identified a TPH2 homolog on human chromosome 12
[GenBank: AY098914]. Also SNPs on TPH2 have now been
detected [e.g., Harvey et al., 2004] but unfortunately after
the completion of the present study, so that this promising
candidate gene could not be considered.
Beside nicotine addiction, the TPH1-gene has been found to
be related to impulsive-aggressive personality traits [Rujescu
et al., 2002; Hennig et al., 2004], as well as behaviors including
suicide which reflects an extreme form of auto-aggression
[Nielsen et al., 1994; Mann et al., 1997; Abbar et al., 2001;
Souery et al., 2001]. Findings from molecular genetics support
prior results from neurochemical studies indicating that
aggression as well as impulsivity is marked by a dysfunctional
Nicotine Dependence and Personality
serotonergic system [e.g., Asberg and Traskman, 1981; Brown
and Linnoila, 1990]. Moreover, there is strong evidence from
the literature that impulsivity [Reuter et al., 2002a] as well
as unsocialized-aggressive behaviors [Zuckerman, 1993], are
related to drug addiction. In sum, these findings suggest a
pleiotropic effect of the TPH1 gene: i.e., the TPH1 gene exerts a
number of influences, affecting, at least, two different phenotypes, nicotine addiction and personality.
The aim of the present study was twofold. First, to further
investigate the role of the 5-HT system on nicotine dependence
and smoking related behaviors. This was done by attempting to
replicate the results by Sullivan et al. [2001] and Lerman et al.
[2001] who reported an association between the THP1 polymorphism C779A and smoking behavior. Both research groups
claimed the necessity of a replication study. The second aim
was to look for an association of the TPH1 gene with the
personality trait of aggressiveness with the aim of detecting a
drug-prone personality trait.
MATERIALS AND METHODS
Sample
The sample of the genetic association study consisted of unrelated subjects (N ¼ 252) of the Giessen Gene Brain Behavior
Project (125 men and 127 women, age: M ¼ 25.43, SD ¼ 5.71)
of whom 108 were smokers and 144 were nonsmokers. All
participants were Caucasian students of German ancestry
without any history of psychopathology or drug abuse (except
of nicotine) who voluntarily participated in the study after
having been informed about the aims of the study and after
having given their written informed consent. There was no
selective dropout because everyone asked agreed to participate. For a subgroup of subjects (N ¼ 200), questionnaire
measures of the personality trait aggression-hostility were
available. The study was approved by the ethics committee of
the German Psychologist Association. As the 5-HT system
seems to be involved in cognitive processes [e.g., Richter-Levin
and Segal, 1996; for a review see Buhot, 1997; Nathan et al.,
2000], by using the homogenous group of university students
the risk of confounding the results with intellectual ability was
reduced.
21
Genetic Analyses
DNA was extracted from buccal cells to avoid a selective
exclusion of subjects with blood and injection phobia. Purification of genomic DNA was performed with a standard
commercial extraction kit (High Pure PCR Template Preparation Kit; Roche Diagnostics, Mannheim, Germany). Genotyping of the TPH A779C polymorphism was performed by
real-time PCR using fluorescence melting curve detection
analysis by means of the Light Cycler System (Roche
Diagnostics). By means of the melting curve analyses SNPs
could be detected without conducting gel electrophoresis
and ensuing sequencing after amplification. The primers
and hybridization probes used (TIB MOLBIOL, Berlin,
Germany) and the PCR protocols were as follows: forward
primer: 50 -CTTATATGTGTGAGTCTGAGTGG-30 ; reverse primer: 50 -GGACATGACCTAAGAGTTCATGGCA-30 ; acceptor
hybridization probe: 50 -LCRed640-CACGCTGCAGTGCTTAACATACGTTTATAA-phosphate-30 ; donor hybridization probe:
50 -CTGAAAGAGAGGTACAAGTT-fluorescein-30 . The PCR
run comprised 55 cycles of denaturation (958C, 0 sec, ramp
rate 208C per sec), annealing (608C, 10 sec, ramp rate 208C per
sec) and extension (728C, 10 sec, ramp rate 208C per sec) which
followed an incubation period of 10 min to activate the
FastStart Taq DNA Polymerase of the reaction mix (Light
Cycler FastStart DNA Master Hybridization Probes, Roche
Diagnostics). After amplification, a melting curve was generated by keeping the reaction time at 408C for 2 min and then
heating slowly to 958C with a ramp rate of 0.28C per sec. The
fluorescence signal was plotted against temperature to yield
the respective melting points (Tm) of the two alleles. Tm for the
A allele was 51.478C (SEM ¼ 0.07) and 56.998C (SEM ¼ 0.06)
for the C allele.
Statistics
Analyses of variance tested for possible associations between
the TPH1-gene and smoking/personality. Due to the fact that
the distribution of FTND scores is nonnormal and variancehomogeneity is not warranted, in addition nonparametric
Kruskal–Wallis-H-tests were also performed.
RESULTS
Measures of Nicotine Addiction
The degree of nicotine dependence was measured by the
Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton
et al., 1991]. Dependent variables comprised: the total FTND
score (FTND); the smoking categories suggested for the
FTND (FTND-CAT: 0, nonsmoker; 1–2, weak dependence;
3–5, medium dependence; 6–7, strong dependence; 8–10,
very strong dependence) [Fagerstrom and Schneider, 1989];
an aggregation of the FTND categories (FTND-adjCAT)
which separates nonsmokers (FTND ¼ 0) from light smokers
(FTND ¼ 1 or FTND ¼ 2) and addicted smokers (FTND > 2);
and finally the categorical item 4 of the FTND assessing the
average daily cigarettes consumed (0, nonsmokers; 1–10, 1;
11–20, 2; 21–30, 3; >30, 4).
Measures of Impulsivity-Aggressiveness
The personality trait of aggression-hostility was measured
by applying the Buss–Durkee-Hostility-Inventory (BDHI)
Buss and Durkee [1957], which is one of the most frequently
used clinical instrument for the assessment of aggression related behaviors. The questionnaire consists of eight subscales,
assault, indirect hostility, irritability, negativism, resentment,
suspicion, verbal hostility, and guilt.
The distributions of genotype and allele frequencies of the
TPH A779C polymorphism are shown in Table I. The genotype
distribution was in Hardy–Weinberg equilibrium (TPH1:
w2 ¼ 0.01, df ¼ 1, P ¼ 0.904). With respect to the TPH1 SNP,
the proportion of the less common A-allele was 38.10% and of
the more common C allele 61.90%.
Results of the ANOVAs and the Kruskal–Wallis-H tests
yielded significant associations between the TPH A779C SNP
and all indicators of progression to nicotine addiction. Mean
FTND raw scores, mean FTND categories, mean aggregated
FTND categories, and mean cigarettes smoked per day were
highest in subjects with the AC genotype (see Table II). There
was neither a main effect for gender nor an interaction of
genotype gender.
TABLE I. Genotype and Allele Frequencies of the
TPH A779C Polymorphism (N ¼ 252)
TPH A779C
AA
AC
CC
A-allele
C-allele
36 (14.28%)
120 (47.62%)
96 (38.10%)
192 (38.10%)
312 (61.90%)
22
Reuter and Hennig
TABLE II. Associations Between the Degree of Nicotine Dependence and the
TPH A779C Polymorphism
FTND
AA
AC
CC
FTND-CAT
AA
AC
CC
FTND-adjCAT
AA
AC
CC
Cig/day
AA
AC
CC
N
M
SEM
ANOVA
Kruskall–Wallis-H-test
36
120
96
0.64
1.73
0.98
0.25
0.24
0.20
F ¼ 4.68, df ¼ 2,249, P ¼ 0.010
w2 ¼ 8.01, df ¼ 2, P ¼ 0.018
36
120
96
0.39
0.88
0.56
0.13
0.11
0.10
F ¼ 4.16, df ¼ 2,249, P ¼ 0.017
w2 ¼ 7.49, df ¼ 2, P ¼ 0.024
36
120
96
0.33
0.72
0.48
0.11
0.08
0.08
F ¼ 4.35, df ¼ 2,249, P ¼ 0.014
w2 ¼ 7.67, df ¼ 2, P ¼ 0.022
36
120
96
0.39
0.79
0.52
0.128 F ¼ 3.45, df ¼ 2,249, P ¼ 0.033
0.096
0.092
w2 ¼ 6.61, df ¼ 2, P ¼ 0.037
FTND, Fagerstrom Test of Nicotine Dependence (FTND) [Heatherton et al., 1991].
FTND-CAT [smoking categories suggested for the FTND; Fagerstrom and Schneider, 1989]: 0, nonsmoker; 1–2,
weak dependence; 3–5, medium dependence; 6–7, strong dependence; 8–10, very strong dependence.
FTND-adjCAT (aggregation of the FTND categories): separating nonsmokers (FTND ¼ 0) from light smokers
(FTND ¼ 1 or FTND ¼ 2) and addicted smokers (FTND > 2).
Cig/day (FTND item 4: average daily cigarettes consumed): 0, nonsmokers; 1–10, 1; 11–20, 2; 21–30, 3; >30, 4.
With respect to personality, two subscales indirect hostility
and negativism were significantly associated with the TPH1
gene (see Table III). For both subscales, mean aggressionhostility scores were highest in the heterozygous AC group and
lowest in the CC group. There were no significant interaction
effects genotype gender observable but a single significant
gender effect for the irritability scale, showing higher irritability scores for women than men (men: M ¼ 4.84, women:
5.76, F(1,199) ¼ 5.42, P ¼ 0.021). In addition, two-factorial analyses of variance were calculated with the factors genotype and
BDHI subscales after dichotomizing the personality measures,
but no significant interaction effects were observed.
DISCUSSION
Previous studies demonstrate that nicotine consumption by
smoking leads to an increase in 5-HT levels, and given the fact
that 5-HT plays a crucial role in the regulation of mood and
impulsivity, it was hypothesized that the serotonergic system
is also involved in nicotine dependence. It was proposed that
candidate genes for nicotine dependence should be investigated to elucidate the biological basis of smoking behavior and
smoking abuse. Moreover, a dysfunctional 5-HT system has
been demonstrated to be a prominent biological factor influencing personality traits related to aggression. These findings
indicate a pleiotropic effect of the 5-HT system by influencing
nicotine addiction as well as specific personality traits.
TABLE III. Significant Associations Between the BDHI
Subscales and the TPH A779C Polymorphism
M
SEM
F
df
P
36
120
96
5.28
5.50
4.64
0.41
0.19
0.22
4.38
2,197
0.014
36
120
96
2.75
2.89
2.35
0.29
0.15
0.16
3.10
2,197
0.047
N
Indirect hostility
AA
AC
CC
Negativism
AA
AC
CC
The present study investigated one of the most prominent
SNPs of the serotonergic system, TPH A779C for such a
pleiotropic effect. TPH plays a crucial role in 5-HT biosynthesis
and therefore regulates the availability of 5-HT. With respect
to the TPH1 polymorphism, previous findings that found associations with smoking related behaviors and nicotine addiction
could be corroborated. The dilemma is that all three studies
who investigated the role of the TPH1 gene on nicotine addiction, the study of Sullivan et al. [2001], Lerman et al. [2001],
and our own study, differ with respect to the relative importance of the respective genotypes/alleles or the relevance of
the TPH1 gene for different indicators of nicotine addiction.
Sullivan et al. [2001] found that the A-allele is significantly
more prevalent in smokers than in nonsmokers, whereas
Lerman et al. [2001] could not find an association between the
A-allele and smoking initiation. But Lerman et al. [2001]
reported a negative linear relationship between the number of
A-alleles and the age of smoking initiation. Both studies did not
find an association between the A779C polymorphism and
progression to nicotine dependence. However, our own results
found that the heterozygous AC genotype is associated with
higher degrees of nicotine dependence as measured by the
FTND and this irrespectively of the dependent variable used
(FTND raw scores, FTND categories, FTND aggregated categories discriminating nonsmokers from light smokers and
addicted smokers, number of cigarettes smoked per day). The
result indicating highest prevalence of nicotine addiction in the
heterozygous TPH1 group can be interpreted as a phenomenon
called heterosis. Molecular heterosis refers to a situation in
which the phenotype is greater (positive heterosis) or lesser
(negative heterosis) for heterozygotes than for either homozygote [Comings and MacMurray, 2000]. Lee [2003] already
had reported a gender-specific molecular heterosis for the
DRD2 TAQ IA polymorphism with respect to nicotine addiction. With respect to the TPH1 gene the heterosis effect was not
gender-specific. In men as well as in women the AC genotype
was associated with higher nicotine addiction.
Sullivan et al. [2001] used the FTQ which shares many items
with the FTND to assess progression to nicotine dependence.
They compared within the group of smokers those with high
FTQ scores with those having a low FTQ score with respect to
the genotype/allele distributions. Such a transformation to a
Nicotine Dependence and Personality
lower scale level is always related to a loss of information. This
may explain the negative results in the Sullivan et al. study. In
our study, we evaluated the FTND raw scores as a dependent
variable in an ANOVA approach and therefore maintained the
total variance in the dependent variable. Although Lerman
et al. [2001] did not find a significant association between the
TPH1-gene and progression to nicotine dependence they at
least reported highest FTND scores in smokers with the AC
genotype which supports our own findings. The method of
comparing nonsmokers with smokers yields the risk of contaminating possible associations between a gene loci and
smoking behavior by including the group of light smokers into
the group of heavy smokers. This may explain why Lerman
et al. [2001] did not find any association between the TPH1gene and smoking initiation. Despite of the reported differences across the TPH1-smoking studies, all three studies
implicate unequivocally an association of the TPH1-gene on
nicotine addiction.
The present study revealed pleiotropic effects of the TPH1gene by influencing besides nicotine addiction also the personality trait of aggression-hostility. The two subcomponents
of the BDHI, which were associated with the A779C polymorphism reflect the neurotic part of aggressive behavior.
By means of a factor analytic approach Hennig et al. [in press]
separated two factors of aggression within the BDHI, one
factor representing neurotic hostility and one factor representing aggressive hostility. In a group of male nonsmokers aggressive hostility was highest in AA carriers and lowest in CC
carriers whereas there was no association between TPH A779C
SNP and neurotic hostility in the group of nonsmokers. In our
group, we could demonstrate that the AC-genotype is associated with neurotic hostility in a mixed group of smokers and
nonsmokers of both genders. This results support previous
studies reporting a strong association between the personality
trait of neuroticism and smoking behavior [Terracciano and
Costa, 1999; Reuter and Netter, 2001].
In sum, the present study yielded further evidence from
molecular genetics for the importance of the 5-HT system—
especially of the TPH1 gene—for nicotine addiction. The report
of a positive heterosis effect for smoking behavior and for the
trait of neurotic hostility stresses the importance of pleiotropic
effects for behavioral genetics. Pleiotropy can account for
phenomena labeled in the addiction research arena as ‘‘drug
prone personality’’ by explaining that the same gene contributes to a behavior (smoking) which has been shown to be
associated with a certain personality trait (neurotic hostility).
Given the fact that the A779C SNP is located on an intron it
remains speculative how this gene can influence addictive
urges or neurotic hostility. The TPH1 gene seems to be in
linkage disequilibrium with an, until now, unidentified functional gene influencing the availability of 5-HT. Low levels of
5-HT have been related to aggressive behaviors and there is a
moderating influence of 5-HT on DA availability [e.g., Porras
et al., 2002], which is crucial for the incentive motivation to
consume nicotine [Reuter et al., 2002b].
ACKNOWLEDGMENTS
23
Brown GL, Linnoila MI. 1990. CSF serotonin metabolite (5-HIAA) studies
in depression, impulsivity, and violence. J Clin Psychiatry 51(Suppl):
31–41.
Buhot MC. 1997. Serotonin receptors in cognitive behaviors. Curr Opin
Neurobiol 7:243–254.
Buss AH, Durkee A. 1957. An inventory for assessing different kinds of
hostility. J Consult Psychol 21:343–349.
Comings DE, MacMurray JP. 2000. Molecular heterosis: A review. Mol
Genet Metab 71:19–31.
Fagerstrom KO. 1978. Measuring degree of physical dependence to tobacco
smoking with reference to individualization of treatment. Addict Behav
3:235–241.
Fagerstrom KO, Schneider NG 1989. Measuring nicotine dependence: A
review of the Fagerstrom Tolerance Questionnaire. J Behav Med
12:159–182.
Han L, Nielsen DA, Rosenthal NE, Jefferson K, Kaye W, Murphy D, Altemus
M, Humphries J, Cassano G, Rotondo A, Virkkunen M, Linnoila M,
Goldman D. 1999. No coding variant of the tryptophan hydroxylase gene
detected in seasonal affective disorder, obsessive-compulsive disorder,
anorexia nervosa, and alcoholism. Biol Psychiatry 45:615–619.
Harvey M, Shink E, Tremblay M, Gagne B, Raymond C, Labbe M, Walther
DJ, Bader M, Barden N. 2004. Support for the involvement of TPH2 gene
in affective disorders. Mol Psychiatry 9:980–981.
Heath AC, Madden PA, Slutske WS, Martin NG. 1995. Personality and the
inheritance of smoking behaviour: A genetic perspective. Behav Genet
25:103–117.
Heatherton TF, Kozlowski LT, Frecker RC, Fagerstrom KO. 1991. The
Fagerstrom Test for Nicotine Dependence: A revision of the Fagerstrom
Tolerance Questionnaire. Br J Addict 86:1119–1127.
Hennig J, Reuter M, Netter P, Burk C, Landt O. Two types of aggression are
differentially related to serotonergic acitvity and the A779C TPH
polymorphism. Behav Neurosci (in press).
Hughes JR, Giovino GA, Klevens RM, Fiore MC. 1997. Assessing the
generalizability of smoking studies. Addiction 92:469–472.
Kunugi H, Ishida S, Kato T, Sakai T, Tatsumi M, Hirose T, Nanko S. 1999.
No evidence for an association of polymorphisms of the tryptophan
hydroxylase gene with affective disorders or attempted suicide among
Japanese patients. Am J Psychiatry 156:774–776.
Lee HS. 2003. Gender-specific molecular heterosis and association studies:
Dopamine D2 receptor gene and smoking. Am J Med Genet 118B:55–59.
Lerman C, Caporaso NE, Bush A, Zheng YL, Audrain J, Main D, Shields PG.
2001. Tryptophan hydroxylase gene variant and smoking behavior. Am
J Med Genet B105:518–520.
Mann JJ, Malone KM, Nielsen DA, Goldman D, Erdos J, Gelernter J. 1997.
Possible association of a polymorphism of the tryptophan hydroxylase
gene with suicidal behavior in depressed patients. Am J Psychiatry
154:1451–1453.
Marshall SE, Bird TG, Hart K, Welsh KI. 1999. Unified approach to the
analysis of genetic variation in serotonergic pathways. Am J Med Genet
B88:621–627.
Mihailescu S, Guzman-Marin R, Dominguez MC, Drucker-Colin R. 2002.
Mechanisms of nicotine actions on dorsal raphe serotoninergic neurons.
Eur J Pharmacol 452:77–82.
Nathan PJ, Sitaram G, Stough C, Silberstein RB, Sali A. 2000. Serotonin,
noradrenaline, and cognitive function: A preliminary investigation of
the acute pharmacodynamic effects of a serotonin versus a serotonin and
noradrenaline reuptake inhibitor. Behav Pharmacol 11:639–642.
Nielsen DA, Goldman D, Virkkunen M, Tokola R, Rawlings R, Linnoila M.
1994. Suicidality and 5-hydroxyindoleacetic acid concentration associated with a tryptophan hydroxylase polymorphism. Arch Gen
Psychiatry 51:34–38.
The authors thank Prof. Philip Corr, University of Swansea,
UK, for his advice in editing the manuscript.
Nielsen DA, Jenkins GL, Stefanisko KM, Jefferson KK, Goldman D. 1997.
Sequence, splice site, and population frequency distribution analyses of
the polymorphic human tryptophan hydroxylase intron 7. Brain Res Mol
Brain Res 45:145–148.
REFERENCES
Porras G, Di Matteo V, Fracasso C, Lucas G, De Deurwaerdere P, Caccia S,
Esposito E, Spampinato U. 2002. 5-HT2A and 5-HT2C/2B receptor
subtypes modulate dopamine release induced in vivo by amphetamine
and morphine in both the rat nucleus accumbens and striatum.
Neuropsychopharmacology 26:311–324.
Abbar M, Courtet P, Bellivier F, Leboyer M, Boulenger JP, Castelhau D,
Ferreira M, Lambercy C, Mouthon D, Paoloni-Giacobino A, Vessaz M,
Malafosse A, Buresi C. 2001. Suicide attempts and the tryptophan
hydroxylase gene. Mol Psychiatry 6:268–273.
Asberg M, Traskman L. 1981. Studies of CSF 5-HIAA in depression and
suicidal behaviour. Adv Exp Med Biol 133:739–752.
Reuter M, Netter P. 2001. The influence of personality on nicotine-craving: A
hierarchical multivariate statistical prediction model. Neuropsychobiology 44:47–53.
24
Reuter and Hennig
Reuter M, Netter P, Rogausch A, Sander P, Kaltschmidt M, Dörr A, Hennig
J. 2002a. The role of cortisol suppression on craving for and satisfaction
from nicotine in high and low impulsive subjects. Hum Psychopharmacol
Clin Exp 17:213–224.
Reuter M, Netter P, Toll C, Hennig J. 2002b. Dopamine agonist and
antagonist responders as related to types of nicotine craving and facets
of extraversion. Prog Neuropsychopharmacol Biol Psychiatry 26:
845–853.
Ribeiro EB, Bettiker RL, Bogdanov M, Wurtman RJ. 1993. Effects of
systemic nicotine on serotonin release in rat brain. Brain Res 621:311–
318.
Richter-Levin G, Segal M. 1996. Serotonin, aging and cognitive functions of
the hippocampus. Rev Neurosci 7:103–113.
Rotondo A, Schuebel K, Bergen A, Aragon R, Virkkunen M, Linnoila M,
Goldman D, Nielsen D. 1999. Identification of four variants in the
tryptophan hydroxylase promoter and association to behavior. Mol
Psychiatry 4:360–368.
Rujescu D, Giegling I, Bondy B, Gietl A, Zill P, Moller HJ. 2002. Association
of anger-related traits with SNPs in the TPH gene. Mol Psychiatry
7:1023–1029.
Souery D, Van Gestel S, Massat I, Blairy S, Adolfsson R, Blackwood D, DelFavero J, Dikeos D, Jakovljevic M, Kaneva R, Lattuada E, Lerer B, Lilli
R, Milanova V, Muir W, Nothen M, Oruc L, Papadimitriou G, Propping P,
Schulze T, Serretti A, Shapira B, Smeraldi E, Stefanis C, Thomson M,
Van Broeckhoven C, Mendlewicz J. 2001. Tryptophan hydroxylase
polymorphism and suicidality in unipolar and bipolar affective disorders: A multicenter association study. Biol Psychiatry 49:405–409.
Spanagel R, Weiss F. 1999. The dopamine hypothesis of reward: Past and
current status. Trends Neurosci 22:521–527.
Sullivan PF, Jiang Y, Neale MC, Kendler KS, Straub RE. 2001. Association
of the tryptophan hydroxylase gene with smoking initiation but not
progression to nicotine dependence. Am J Med Genet 105:479–484.
Terracciano A, Costa PT Jr. 1999. Smoking and the five-factor model of
personality. Addiction 99:472–481.
Walther DJ, Peter JU, Bashammakh S, Hortnagl H, Voits M, Fink H, Bader
M. 2003. Synthesis of serotonin by a second tryptophan hydroxylase
isoform. Science 299:76.
Zuckerman M. 1993. P-impulsive sensation seeking and its behavioral,
psychophysiological and biochemical correlates. Neuropsychobiology
28:30–36.
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effect, polymorphism, nicotine, tph, dependence, pleiotropic, personality, a779c
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