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The tryptophan hydroxylase 1 (TPH1) gene schizophrenia susceptibility and suicidal behavior A multi-centre caseЦcontrol study and meta-analysis.

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RESEARCH ARTICLE
Neuropsychiatric Genetics
The Tryptophan Hydroxylase 1 (TPH1) Gene,
Schizophrenia Susceptibility, and Suicidal Behavior:
A Multi-Centre Case–Control Study and Meta-Analysis†
Peter Saetre,1* Per Lundmark,2 August Wang,3 Thomas Hansen,4,5 Henrik B. Rasmussen,4
Srdjan
Djurovic,6,7,8 Ingrid Melle,6,7,8 Ole A. Andreassen,6,7,8 Thomas Werge,4 Ingrid Agartz,1,6,9
Hakan Hall,1 Lars Terenius,1 and Erik G. J€onsson1
1
Department of Clinical Neuroscience, HUBIN Project, Karolinska Institutet and Hospital, Stockholm, Sweden
2
Department of Medical Sciences, Molecular Medicine, Uppsala University, Uppsala, Sweden
Mental Health Center Amager, Copenhagen University Hospital, Copenhagen, Denmark
3
4
Research Institute of Biological Psychiatry, Copenhagen University Hospital, Mental Health Centre Sct. Hans, Roskilde, Denmark
5
Centre for Pharmacogenomics, University of Copenhagen, Copenhagen N, Denmark
Institute of Psychiatry, University of Oslo, Oslo, Norway
6
7
Department of Medical Genetics, Ulleval University Hospital, Oslo, Norway
8
Department of Psychiatry, Ulleval University Hospital, Oslo, Norway
9
Department of Psychiatric Research, Diakonhjemmet Hospital, Oslo, Norway
Received 23 January 2009; Accepted 7 May 2009
How to Cite this Article:
Serotonin (5-hydroxytryptamin; 5-HT) alternations has since
long been suspected in the pathophysiology of schizophrenia.
Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH)
is the rate-limiting enzyme in the biosynthesis of 5-HT, and
sequence variation in intron 6 of the TPH1 gene has been
associated with schizophrenia. The minor allele (A) of this
polymorphism (A218C) is also more frequent in patients who
have attempted suicide and individuals who died by suicide, than
in healthy control individuals. In an attempt to replicate previous
findings, five single nucleotide polymorphisms (SNPs) were
genotyped in 837 Scandinavian schizophrenia patients and
1,473 controls. Three SNPs spanning intron 6 and 7, including
the A218C and A779C polymorphisms, were associated with
schizophrenia susceptibility (P ¼ 0.019). However there were no
differences in allele frequencies of these loci between affected
individuals having attempted suicide at least once and patients
with no history of suicide attempts (P ¼ 0.84). A systematic
literature review and meta-analysis support the A218C polymorphism as a susceptibility locus for schizophrenia (odds ratio 1.17,
95% confidence interval 1.07–1.29). Association studies on suicide attempts are however conflicting (heterogeneity index
I2 ¼ 0.54) and do not support the A218C/A779C polymorphisms
being a susceptibility locus for suicidal behavior among individuals diagnosed with a psychiatric disorder (OR ¼ 0.96
[0.80–1.16]). We conclude that the TPH1 A218/A779 locus increases the susceptibility of schizophrenia in Caucasian and
Asian populations. In addition, the data at hand suggest that
the locus contributes to the liability of psychiatric disorders
characterized by elevated suicidal rates, rather than affecting
Ó 2009 Wiley-Liss, Inc.
Saetre P, Lundmark P, Wang A, Hansen T,
Rasmussen HB, Djurovic S, Melle I,
Andreassen OA, Werge T, Agartz I, Hall H,
Terenius L, J€
onsson EG. 2010. The
Tryptophan Hydroxylase 1 (TPH1) Gene,
Schizophrenia Susceptibility, and Suicidal
Behavior: A Multi-Centre Case–Control
Study and Meta-Analysis.
Am J Med Genet Part B 153B:387–396.
†
This article was published online on 12 June 2009. An error was
subsequently identified. August Wang was not included in the list of
authors. This notice is included in the online and print versions to
indicate that both have been corrected 11 February 2010.
Additional Supporting Information may be found in the online version of
this article.
Grant sponsor: Copenhagen Hospital Corporation Research Fund; Grant
sponsor: Danish National Psychiatric Research Foundation; Grant
sponsor: Danish Agency for Science; Grant sponsor: Research Council
of Norway; Grant numbers: 147787, 167153; Grant sponsor: Eastern
Norway Health Authority (Helse Øst RHF); Grant number: 123/2004;
Grant sponsor: Swedish Research Council; Grant number: K2007-62X15077-04-1; Grant sponsor: The Knut and Alice Wallenberg Foundation;
Grant number: KAW 2005.0256.
*Correspondence to:
Dr. Peter Saetre, R5:00, Stockholm SE-171 76, Sweden.
E-mail: peter.saetre@ki.se
Published online 12 June 2009 in Wiley InterScience
(www.interscience.wiley.com)
DOI 10.1002/ajmg.b.30991
387
388
suicidal behavior of individuals suffering from a psychiatric
disorder. Ó 2009 Wiley-Liss, Inc.
Key words: tryptophan hydroxylase 1 gene (TPH1); schizophrenia; suicidal behavior; case–control association study; metaanalysis
INTRODUCTION
A role for serotonin (5-hydroxytryptamin; 5-HT) alterations in the
pathophysiology of schizophrenia has long been suspected. 5-HT
agonists have psychogenic effects [Lieberman et al., 1998;
Abi-Dargham, 2007], and positive symptoms, like delusions
and hallucinations, are thought to occur after activation of the
5-HT2 receptors [Aghajanian, 1994; Schotte et al., 1996; Sodhi
and Sanders-Bush, 2004]. Atypical anti-psychotic drugs are
potent 5-HT2A receptor antagonists, but relatively weak dopamine
D2 receptor antagonists [Schotte et al., 1996]. In addition, postmortem samples from schizophrenia patients show a reduced
density of 5 -HT2A receptors in prefrontal cortex, suggesting that
5-HT dysfunction is a part of the pathophysiology of the
disease [Burnet et al., 1996; Dean et al., 1999; Matsumoto et al.,
2005].
Suicidal behavior is a well-established clinical feature of schizophrenia [Tandon et al., 2008]. The lifetime suicide prevalence in
schizophrenia has been estimated to about 5.6%, and young
patients, early in the course of schizophrenia, are more likely to
commit suicide than older patients [Palmer et al., 2005]. However,
the suicide risk remain high also later in life [Carlborg et al., 2008].
Poor adherence to treatment, previous depressive disorders and/or
suicide attempts, fear of mental disintegration and affective symptoms increases the risk for future suicide attempts [Hawton et al.,
2005]. The curable effects of anti-depressive and anti-anxiety drugs
that modulate 5-HT, suggests that 5-HT dysfunction may underlie
suicidal behavior associated with schizophrenia and other psychiatric disorders. Moreover, low cerebrospinal fluid (CSF) concentrations of the major 5-HT metabolite
5-hydroxyindole acetic acid
(5-HIAA) in suicide attempters [Asberg, 1997; Mann and Malone,
1997], as well as the pronounced differences with respect to the
density of 5-HT transporter sites and several 5-HT receptor subtypes among suicidal individuals [Arango et al., 1995; Mann et al.,
2000; Anisman et al., 2008], provide additional support for a
general link between 5-HT dysfunction and suicidal behavior.
Tryptophan hydroxylase (tryptophan 5-monooxygenase; TPH)
is the rate-limiting enzyme in the biosynthesis of 5-HT. Consequently, dysfunction in this enzyme has been hypothesized to be
involved in pathological disturbances of the 5-HT system. There
are two genes encoding TPH: TPH1 (11p15.3–p14) and TPH2
(12q21.1). In rodents TPH2 is the predominant isoform of the
enzyme in the adult central nervous system (CNS), whereas TPH1 is
primarily active in the periphery [Sakowski et al., 2006]. However,
TPH1 is abundantly expressed in the brain during the late prenatal
period, and appears to modulate the effect of serotonin on neuron
number and growth [Rind et al., 2000; Nakamura et al., 2006]. In
humans both TPH1 and TPH2 are expressed in cortex, hypothalamus, thalamus, hippocampus, amygdala, cerebellum, and raphe
nuclei [Zill et al., 2007].
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
TPH1 is the best studied of the two genes so far, and numerous
studies have demonstrated association between single nucleotide
polymorphisms (SNPs) in the TPH1 gene and the liability of
psychiatric disorders and suicidal behavior. A218C (rs1800532)
and A779C (rs1799913) are two polymorphisms located in intron
6 of the gene, which are in complete, or almost complete, linkage
disequilibrium (LD) in Caucasian populations. The A218-allele has
consistently been associated with an increased liability of schizophrenia across multiple ethnic groups [Watanabe et al., 2007], and
the association show strong epidemiological credibility [Allen et al.,
2008]. The association between A218C/A779C and suicidal
behavior has been extensively studied in both European and Asian
populations [Rujescu et al., 2003; Bellivier et al., 2004]. Also the
latest meta-analysis, contrasting allele frequencies between suicide
attempters suffering from different psychiatric disorders or individuals who died by suicide (often of unknown mental health
status) and unaffected controls in 34 independent studies, demonstrates an overall association between the A218C/A779C polymorphisms and suicidal behavior [Li and He, 2006]. This supports
the involvement of TPH1 also in the pathogenesis of suicidal
behavior.
In the present study five TPH1 single nucleotide polymorphisms
(SNPs) were genotyped in three Scandinavian case–control samples
comprising 837 patients suffering from schizophrenia and
related disorders and 1,473 controls. For patients with retrospective
information on suicidal behavior (n ¼ 738), TPH1 polymorphisms
were also analyzed for an association with suicide attempts. In
addition we reviewed the literature for TPH1 association studies
with schizophrenia and suicidal attempts among patients diagnosed with a psychiatric disorder, and meta-analyzed previously
published reports. Our study is in agreement with the previously
published literature, suggesting that the A218C locus is associated
with schizophrenia but not with suicidal behavior among individuals affected by schizophrenia, affective, alcoholism, or personality
related disorders.
MATERIALS AND METHODS
Clinical Samples
The clinical samples originate from the Scandinavian Collaboration
on Psychiatric Etiology (SCOPE) and were collected in Denmark
(DK), Norway (NO), and Sweden (SE). Affected individuals diagnosed with schizophrenia (n ¼ 734), schizoaffective disorder
(n ¼ 87), or schizophreniform disorder (n ¼ 16), according to
ICD-10 (DK) or DSM-III-R/DSM-IV (NO and SE), were compared
to unrelated matched controls (Table I). All individuals in the study
were of Caucasian origin and detailed descriptions of the samples
have previously been reported [Hansen et al., 2007; J€
onsson et al.,
2008a; K€ahler et al., 2008]. One hundred fifty one affected and
130 control individuals from the Swedish sample were included in a
previous association analysis between TPH1 and schizophrenia
[Zaboli et al., 2006b].
Patients (n ¼ 738) were assessed for presence or absence of
suicide attempts based on record reviews (DK, SE) and interview
data (NO, SE). Any previous self-harm, in combination with
suicidal ideation, documented or reported was regarded as a suicide
SAETRE ET AL.
389
TABLE I. Characteristics of Danish (DK), Norwegian (NE), and
Swedish (SE) Samples Analyzed for Association Between
Tryptophan Hydroxylase 1 (TPH1) Gene Variants and
Schizophrenia and Suicide Attempt Among Affected (Case)
Country
DK
NO
SE
Characteristic
N
Gender (%women)
Agea
Age onseta
Suicide attempters (%)
N
Gender (%women)
Age
Age onset
Suicide attempters (%)
N
Gender (%women)
Age
Age onset
Suicide attempters (%)
Case
420
42.6
43.9 12.3
27.2 8.9
43.5
162
46.3
37.2 10.7
27.6 8.7
27.6
255
37.2
54.1 15.2
26.3 7.2
44.8
Control
1004
41.5
43.2 11.8
177
55.4
38.7 10.3
292
37.7
50.3 10.1
a
Mean standard deviation given for quantitative variables.
attempt. For the present analysis subjects were divided into those
who had made at least one suicide attempt and those who had not
performed any suicide attempt.
The Danish Scientific Committees, the Danish Data Protection
Agency, the Norwegian Scientific-Ethical Committees, the
Norwegian Data Protection Agency, the Ethical Committee of the
Karolinska Hospital, the Stockholm Regional Ethical Committee
and the Swedish Data Inspection Board all approved the study. All
participants had given informed consent prior to inclusion in the
study.
SNP Selection and Genotyping
Based on previous published literature we selected five SNPs
for genotyping. These markers are spanning the TPH1 from
the upstream region (6.5 kbp; rs4537731), through intron
2 (rs211105) and intron 6 (rs1800532, rs1799913) to intron
7 (rs7933505). Genomic DNA was extracted from whole blood
samples, and the selected SNPs were genotyped at the SNP Technology Platform in Uppsala, Sweden (www.genotyping.se), using the
Illumina BeadStation 500GX and the 1536-plex Illumina Golden
Gate assay (Illumina, Inc., San Diego, CA). The sample success rate
was on average 99.7% for the genotyped SNPs and the reproducibility of the genotyping was 100% according to duplicate analysis
of 2.6% of the genotypes.
Literature Search
We performed a meta-analysis of published case–control studies
examining the association between the TPH1 A218C polymorphism (rs1800532) and schizophrenia. In addition we metaanalyzed the association between A218C/A779C polymorphisms
and suicide attempt among individuals diagnosed with a psychiatric disorder. Data were obtained by searching the National Library
of Medicine’s database PubMed up to August 2008, using the search
terms ‘‘tryptophan hydroxylase,’’ ‘‘TPH,’’ and ‘‘schizophrenia’’ or
‘‘suicidal behavior’’ and ‘‘suicide’’, respectively. References cited
in identified studies and reviews were scrutinized to identify
additional work not identified by our initial PubMed search.
We included case–control studies, which were published in a peerreviewed journal, contained independent data that was sufficient
to calculate the odds ratio (OR) and its confidence interval,
and where psychiatric disorder (including schizophrenia) and/or
suicidal behavior had been diagnosed according to the International Classification of Diseases (ICD), Diagnostic and Statistical
manual of Mental disorders (DSM) or Chinese Classification of
Mental Disorders (CCMD) systems. Since our aim was to examine
the association between TPH1 and suicidal behavior independently
of mental health status, we only included studies where genotype
frequencies were available for both suicide (SA) and non-suicide
attempters (NSA) diagnosed with the same psychiatric disorder.
The A218C and A779C polymorphisms are in complete LD (R2 1)
in populations of European descent and thus association studies of
the A218C and A779C (rs1799913) polymorphisms conducted in
Caucasian populations were treated synonymously. In total we
identified 11 studies comparing the frequency of A218C/A779C in
schizophrenia and healthy controls. Of these, five were excluded:
the study of Chotai et al. [2003] and the study of Zaboli et al.
[2006b], which overlapped with the study by Serretti et al. [2001]
and the present Swedish sample, respectively, and the studies of
Shinkai et al. [2000], Chao and Richardson [2002], and Semwal
et al. [2002], who genotyped A779C in Japanese, African-American,
and Indian populations, where theA218C and A779C loci are not
known to be in complete LD. We identified 16 studies that
compared the frequency of A218C/A779C in suicide and nonsuicide attempters diagnosed with the same psychiatric disorder. If
insufficient data were given in the reports, we tried to contact
the corresponding authors by e-mail for additional information.
Despite these efforts, four studies were excluded from the
analysis due to insufficient data. That is, for the studies conducted
by Furlong et al. [1998] and Ho et al. [2000], no data on the
numbers of individuals per TPH1 genotype and suicide/nonsuicide attempters were listed in the original reports. In the study
by Kunugi et al. [1999], the numbers of individuals per TPH1
genotype of non-suicide attempters diagnosed with bipolar
disorder or unipolar depression were not listed. Souery et al.
[2001] matched controls and patients with respect to ethno-geographic origin, but the numbers of individuals per A218C
genotype for matched suicide and non-suicide patients was not
provided.
Statistical Analysis
Hardy–Weinberg (HW) equilibrium was tested in the control
samples using Fisher’s exact test as implemented in PEDSTATS
[Wigginton and Abecasis, 2005]. Linkage disequlibrium (D0 and
R2) between SNP pairs, and haplotype block structure [Gabriel
et al., 2002] were determined with Haploview 4.0 [Barrett et al.,
2005] (Supplementary Fig. 1). The fixation index (FST) was
390
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
calculated for each SNP separately, and all loci combined, in the
control sample with FSTAT, grouping controls by country of origin.
No evidence of population stratification was evident from the data:
the fixation index for all combined loci was 0.001 0.001 (95%
bootstrap confidence interval).
Association analysis comparing allele and genotype frequencies
between affected individuals and controls, and between
suicide attempters and non-attempters within the patient group,
were performed with UNPHASED (version 3.0.9) [Dudbridge,
2003, 2008]. To account for possible population stratification,
we included country of origin as a confounding factor in
the association analyses. Test for heterogeneity between countrieswas performed in a separate analysis, specifying country as a
modifier. Haplotype analysis was carried out with UNPHASED
using all five SNPs, which belonged to one haplotype block.
We chose 0.05 as the level of nominal significance. Correction for
multiple testing was accomplished by permuting the affection
status and presence/absence of suicide attempts (among affected
only), respectively, and recalculating P values for the permuted
data (1,000 permutations). Empirical P values were calculated for
each of the two hypotheses separately, (compensating for five tests),
as the fraction of permutations yielding P values less or equal to the
observed P values.
For the meta-analysis we first calculated crude study-specific
odds ratios (ORs) and 95% confidence intervals (95% CI) for each
study, comparing the minor versus major alleles. We obtained
summary ORs and 95% CI with the random-effects model
[DerSimonian and Laird, 1986], which utilizes weights that incorporate both the within-study and between-study variance. Between
-study heterogeneity was assessed with Cochran’s Chi-squarebased Q statistic, and by the I2 heterogeneity metric. Publication
bias was assessed by examining funnel plot asymmetry [Egger et al.,
1997]. That is, the standard normal deviate was regressed against
the OR estimate precision, and a t-test was used to detect if the
intercept deviated significantly from zero.
RESULTS
Association With Schizophrenia
Three out of five tested markers attained nominal significant
association with the disease (P 0.05), namely rs1800532
(A218C), rs1799913 (A779C), and rs7933505 (Table II). These
markers, which are located in a 1.8 kb segment spanning introns
6 and 7, were in almost complete LD (D0 ¼ 1, R2 0.99) (Fig. S1),
and it was the minor alleles (A) that were over-represented among
affected individuals. The odds ratio (OR) for the most significant
marker rs1799913 was 1.18 for the combined sample with a
95 confidence interval (95 CI) between 1.04 and 1.34. The OR
tended to be larger for the Swedish sample (OR ¼ 1.42) than for the
Norwegian and Danish samples (1.18 and 1.09, respectively).
However, the difference in association strength between countries
of origin was not statistically significant (P ¼ 0.20), and may well
have occurred by chance alone. As expected, the results for the two
markers rs1800532 and rs7933505, which were in very strong LD
with rs1799913, were similar (Table II). The association signal from
the three nominally significant SNPs was globally significant, and
the empirical P-value for attaining three markers with an equally
strong (or stronger) disease association was 0.019 (determined
from 1,000 permutations). Five haplotypes accounted for 99.6% of
the segregating haplotypes in the population. As expected the
haplotype retaining the A alleles of rs1800532, rs1799913 and
rs7933505 (ATAAA) was associated with an increased risk of the
disease (freqSCZ ¼ 0.41, freqCTRL ¼ 0.37; P ¼ 0.019), and a haplotype lacking these alleles (GTCCG) tended to be protective
(freqSCZ ¼ 0.17, freqCTRL ¼ 0.20; P ¼ 0.049).
Association With Suicidal Behavior in Affected
Individuals
To examine whether the TPH1 polymorphisms were associated
with suicidal behavior in affected individuals, we tested allele and
TABLE II. Allele Frequencies, Genotype Counts, and Association Statistics for Single Nucleotide Polymorphisms (SNPs) in the Tryptophan
Hydroxylase 1 (TPH1) Gene and Schizophrenia in Swedish (SE), Norwegian (NO) and Danish (DK) Case–Control Samples
Polymorphism
SNP ID
rs4537731
rs211105
rs1800532
rs1799913
rs7933505
1/2b
A/G
T/G
C/A
C/A
G/A
MAFc
0.43
0.25
0.37
0.37
0.38
HWd
0.92
0.09
0.82
0.54
1.00
Case/control
1/1
304/470
468/839
290/570
289/570
289/565
1/2
373/725
309/520
391/691
391/694
391/690
*Indicate nominal significance (P < 0.05).
a
OR corresponds to allele association.
Major/Minor allele.
Minor allele frequency.
d
P-value from test of Hardy–Weinberg equilibrium among control subjects.
e
P-value for test of heterogeneity between samples.
b
c
Disease
association
(P-value)
2/2
157/275
53/102
149/203
145/196
154/211
Allele
0.169
0.991
0.016*
0.010*
0.015*
Genotype
0.075
0.836
0.043*
0.024*
0.042*
Odds ratioa
All
0.92
1.00
1.17
1.18
1.17
SE
0.82
1.04
1.39
1.42
1.35
NO
1.03
1.17
1.18
1.18
1.19
DK
0.93
0.93
1.07
1.09
1.08
Heterogeneitye
0.56
0.41
0.19
0.20
0.30
SAETRE ET AL.
391
TABLE III. Genotype Counts and Association Statistics for Single Nucleotide Polymorphisms (SNPs) in the Tryptophan Hydroxylase 1
(TPH1) Gene and Suicidal Behavior in Swedish (SE), Norwegian (NO), and Danish (DK) Schizophrenia Patients
SA/NSAa
SNP
ID
rs4537731
rs211105
rs1800532
rs1799913
rs7933505
Suicide attempt
association
(P-value)
Allelec
A/G
T/G
C/A
C/A
G/A
1/1
105/154
163/247
99/154
99/154
99/153
1/2
136/202
110/163
150/202
150/202
150/202
2/2
58/80
24/25
50/77
49/77
50/82
Allele
0.654
0.263
0.842
0.896
0.905
Genotype
0.761
0.342
0.848
0.830
0.749
Odds ratiob
All
1.05
1.15
1.02
1.01
0.99
SE
0.72
0.92
1.55
1.55
1.49
NO
1.93
1.82
0.76
0.76
0.76
DK
1.08
1.10
0.86
0.85
0.82
Heterogeneityd
0.04*
0.24
0.06
0.06
0.06
*Indicate nominal significance (P < 0.05).
a
Suicide attempt/No suicide attempt.
OR corresponds to allele association.
Major/minor allele (1/2).
d
P-value for test of heterogeneity between samples.
b
c
genotype association between the five genotyped SNPs and
presence/absence of suicide attempts in affected individuals
(n ¼ 738). The association between TPH1 and suicidal behavior
was contradictory in the three samples. That is, four of the five
investigated SNPs showed divergent effects between countries of
origin (Pheterogeneity 0.06, Table III), and no evidence was found
for a general association between any of the SNPs and presence of
suicide attempts among affected individuals in the Scandinavian
population (P-value for allele and genotype association >0.25,
Table III). Nor did haplotype analysis reveal any segregating
segment that was consistently associated with suicide attempts
among affected individuals.
Meta-Analysis of A218C and Schizophrenia
Our meta-analysis of seven independent studies [Paik et al., 2000;
Hong et al., 2001; Serretti et al., 2001; Sekizawa et al., 2004; Liu et al.,
2006; Watanabe et al., 2007; present study], including a total of
FIG. 1. Retrospective meta-analysis of the association between the tryptophan hydroxylase 1 (TPH1) A218C allele and schizophrenia. Odds ratios
(on a logarithmic scale) are presented for seven sequential analyses of accumulating data. The first point represents the odds ratio from the study
of Paik et al. [2000] only, the second point the odds ratio from a meta-analysis of the combined data from Paik et al. [2000] and Hong et al. [2001].
The last point (This study) represents the pooled estimate from all included studies. The size of the circle is inversely proportional to the variance of
the estimate, and whiskers represent the 95% confidence intervals.
392
AMERICAN JOURNAL OF MEDICAL GENETICS PART B
FIG. 2. Forest plot of ln (odds ratio) from the association between the tryptophan hydroxylase 1 (TPH1) A218C/A779C alleles and presence of
suicidal attempts among individuals diagnosed with a psychiatric disorder (1, alcohol abuse/dependence; 2, major depression; 3, bipolar affective
disorder; *, schizophrenia). The size of the circle is inversely proportional to the variance of the estimate, and whiskers represent the 95%
confidence intervals. The summary estimate of all studies is indicated by the diamond to the right.
2,513 cases and 3,093 controls, indicated that the A218 allele is
associated with schizophrenia (P ¼ 0.0008) (Table SI). A retrospective analysis of cumulative data show that the odds ratio of the
combined data is starting to converge at an estimate of 1.17 (95 CI:
1.07–1.29; Fig. 1), which is similar to the findings of the present
study on its own. In all seven individual studies the A allele was more
frequent in affected individuals than in controls, and the between
study heterogeneity was limited (I2 ¼ 21.0, PQ ¼ 0.27). No evidence
of publication bias was evident from the test of funnel plot
asymmetry (P ¼ 0.57).
Meta-Analysis of A218C/A779C and Suicidal
Behavior Among Individuals Affected With a
Psychiatric Disorder
The meta analysis of 12 studies [Nielsen et al., 1994, 1998; Mann
et al., 1997; Bellivier et al., 1998; Tsai et al., 1999; Paik et al., 2000;
Hong et al., 2001; Koller et al., 2005; Liu et al., 2006; Viana et al.,
2006; Wilson et al., 2009; present study], including 1,272 suicide
attempters and 1,727 non suicide attempters diagnosed with a
psychiatric disorder, showed no evidence for a consistent association between the A218C/A779C locus and suicidal behavior
(P ¼ 0.70, Fig. 2). The patients included in the meta-analysis were
diagnosed with schizophrenia (three studies), bipolar disorder
(two), major depression (two), alcohol abuse/dependence
(three), or borderline personality disorder (one). Two studies
included samples of patients from several diagnostic categories
(Table SII). The summary odds ratio from all studies was close
to one (0.96, 95 CI: 0.80–1.16), and results from individual
studies were contradictory with a large heterogeneity in response
(I2 ¼ 53.6, PQstudy ¼ 0.01). Although there were differences in the
fraction of patients that had attempted suicide between diagnostic
groups, there were no significant differences in allele association
with suicidal behavior between diagnostic groups (PQdiagnosis ¼
0.12). In addition, we found no evidence of publication bias in the
test of funnel plot asymmetry (P ¼ 0.41). Thus the observed heterogeneity in odds ratio of the association between the A alleles of
the A218C/A779C locus and suicidal behavior is likely to reflect
random within and between study variation (Pheterogeneity with
random model ¼ 0.19).
DISCUSSION
There was a significant association between TPH1 and schizophrenia in the examined Scandinavian population, and it was the
minor alleles of the three tightly linked markers spanning intron six
and seven (rs1800532, rs1799913, and rs7933505) that were overrepresented in affected individuals, in both single-marker and
haplotype analysis. These results are in agreement with our metaanalysis of previously reported studies (in total 2,513 cases and
3,093 controls), where the A218 (rs1800532 A) allele shows a
consistent association with increased susceptibility of schizophrenia. The estimated odds ratio of 1.17 (95 CI 1.03–1.32) from
our Scandinavia population is similar to the summary estimate
from all published studies (including this). Moreover, as of the two
last well-powered studies, the estimated effect of the locus appears
to be converging towards an odds ratio close to 1.17. As expected
these results are similar to another recent meta-analyses of the
A218C polymorphism [Watanabe et al., 2007], and the accumulated evidence strongly suggest that there is an association between
TPH1 gene variation and susceptibility of schizophrenia. However
no function of the A218C locus, or any other polymorphisms in LD
with this SNP, is known. In addition, mouse models give limited
clues to a possible link between TPH1 and mental health in humans,
as near depletion of 5-HT in the central and/or peripheral nervous
system of knockout TPH1 and TPH2 mice, appears to cause only
SAETRE ET AL.
subtle changes in behavior [Cote et al., 2003; Savelieva et al., 2008].
Thus whereas the epidemiological evidence for TPH1 as a susceptibility gene for schizophrenia appears to be solid, we are still
awaiting the identification of a causative mutation and the
biological mechanisms by which it affects schizophrenia
susceptibility.
There was no evidence for a consistent association between
TPH1 and suicidal behavior in individuals affected with schizophrenia in the Scandinavian population. Although these results are
in agreement with previous studies on suicidal behavior in schizophrenia, which reported no differences in A218C allele frequencies
between suicide attempters and non-attempters [Paik et al., 2000;
Hong et al., 2001; Liu et al., 2006], the results are at odds with the
suggestion that TPH1 polymorphisms affects suicidal behavior
independently of mental health status [Courtet et al., 2005]. Over
90% of suicide victims or suicide attempters have been diagnosed
with a psychiatric illness, most commonly a mood disorder
[Beautrais et al., 1996; Shaffer et al., 1996]. Consequently, association studies contrasting healthy controls with suicide attempters or
individuals who died by suicide will almost inevitable confound
mental health status and suicidal behavior. To investigate whether
the established association between A218C/A779C and suicidal
behavior, based on comparisons between patients who performed
a suicide attempt or died by suicide and healthy controls [Li and He,
2006], has primarily been driven by a statistical confounding, or
whether there are evidence of an independent effect of the locus on
suicidal behavior, we searched the literature for studies which had
compared allele frequencies in suicidal and non-suicidal patients
diagnosed with a psychiatric illness.
We identified 12 studies, which had compared the allele frequencies of A218C/A779C in the suicidal attempters and nonattempters diagnosed with a psychiatric disorder. A meta-analysis
of in total 3,000 patients provided no evidence for an association
between A218C/A779C and suicidal behavior that was independent
of mental health status. In fact, the pooled odds ratio was close to 1
and the heterogeneity between studies appeared to reflect random
between study variation, rather than a diagnostic dependent association. In the light of these results, the simplest interpretation of
the previously reported association between TPH1 and suicidal
behavior is that it has been driven by a statistical confounding with
poor mental health status. If the allele frequencies are consistently
elevated in suicidal individuals suffering from any psychiatric
disorder, then this suggests to us that TPH1 is not only a susceptibility gene for schizophrenia, but also for several other psychiatric
disorders characterized by elevated suicidal behavior. The concept
of shared biological susceptibility to two or more co-morbid
disorders is not new [Palomo et al., 2007], and medication that
affects 5-HT neurotransmission are used to treat a suit of psychiatric disorders, including major depression, anxiety disorders, and
schizophrenia. Reduced cerebrospinal fluid 5-HIAA levels have
been reported to be associated not only with suicide attempts but
also with susceptibility for psychiatric disorders more generally
[J€
onsson et al., 2008b]. Moreover, studies that address the coinheritance of psychiatric disorders have shown shared genetics
behind, for example, schizophrenia and bipolar disorder [Yip et al.,
2008; Lichtenstein et al., 2009] and between major depression and
alcohol dependence [Fu et al., 2002a]. It has also been reported that
393
the heritability of suicidal behavior can be partly attributed to
genetic components underlying psychiatric disorders [Fu et al.,
2002b].
If TPH1 gene variants are associated with mental disorders
characterized by a high suicide rate, then association should occur
between the same TPH1 variants and other psychiatric disorders
than schizophrenia. The relationship between TPH1 A218C/A779C
variation and bipolar disorder, major depression, alcohol dependence and borderline personality disorder has been investigated
with various results. However, hitherto only a restricted number of
studies have been performed for each of these diagnostic categories,
for example, only two studies with in total about 200 patients have
assessed borderline personality disorder [Zaboli et al., 2006a;
Wilson et al., 2009], making meta-analyses premature given the
low odds ratios anticipated. In the future, the correctness of our
hypothesis will be possible to test in meta-analyses with larger
number of studies and samples.
In conclusion, TPH1 is a susceptibility gene for schizophrenia in
the Scandinavian population, but it is not associated with suicidal
behavior within the patient group. These findings are supported by
meta-analyses of previously published reports. The data suggests
that the established association between TPH1 and suicidal behavior may primarily be driven by statistical confounding of suicidal
behavior and mental health status. Thus, another interpretation of
the reported association is that the TPH1 A218C/A779C polymorphisms are associated with increased susceptibility for psychiatric disorders in general, which in turn are characterized by an
increased incidence of suicide.
ACKNOWLEDGMENTS
We thank patients and controls for their participation and express
our gratitude towards health professionals who facilitated our work.
This study was financed in Denmark by grants to TW from the
Copenhagen Hospital Corporation Research Fund, the
Danish National Psychiatric Research Foundation, the Danish Agency for Science, and Technology and Innovation (Centre for
Pharmacogenetics), in Norway from the Research Council of Norway (147787, 167153), the Eastern Norway Health Authority (Helse
Øst RHF 123/2004), Ulleval University Hospital, and University of
Oslo, and in Sweden from the Swedish Research Council (K2007-62X
-15077-04-1, K2007-62X-15078-04-3, K2008-62P-20597-01-3), the
regional agreement on medical training and clinical research between
Stockholm County Council and the Karolinska Institutet, Wallenberg Foundation, and the HUBIN project. We thank
Alexandra
Tylec, Agneta Gunnar, Monica Hellberg, and Kjerstin Lind for
technical assistance. We also thank Kristina Larsson, Tomas Axelsson
and Ann-Christine Syv€anen at the SNP Technology Platform in
Uppsala for performing the genotyping. The SNP Technology
Platform is supported by Uppsala University, Uppsala University
Hospital and by the Knut and Alice Wallenberg Foundation.
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