close

Вход

Забыли?

вход по аккаунту

?

Dopa decarboxylase and tyrosine hydroxylase gene variants in suicidal behavior.

код для вставкиСкачать
American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 147B:308 –315 (2008)
Dopa Decarboxylase and Tyrosine Hydroxylase Gene
Variants in Suicidal Behavior
Ina Giegling,1 Daniel Moreno-De-Luca,2 Dan Rujescu,1** Barbara Schneider,3 Annette M. Hartmann,1
Axel Schnabel,4 Konrad Maurer,3 Hans-Jürgen Möller,1 and Alessandro Serretti2*
1
Department of Psychiatry, Ludwig Maximilians University, Munich, Germany
Institute of Psychiatry, University of Bologna, Bologna, Italy
3
Department of Psychiatry, Psychosomatics, and Psychotherapy, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
4
Institute of Forensic Medicine, Johann Wolfgang Goethe-University, Frankfurt/Main, Germany
2
The dopaminergic system has been previously
associated to behavioral facilitation and aggression, hence making the pathway a good candidate
for suicidal behavior. We studied gene variants
in the tyrosine hydroxylase (rs3842727, rs6356)
and DOPA decarboxylase (rs1451371, rs1470750,
rs998850) genes in a sample of 571 individuals
consisting of 167 German suicide attempters
(affective spectrum n ¼ 107, schizophrenia spectrum n ¼ 35, borderline personality disorder n ¼
25), 92 Caucasian individuals who committed
suicide and 312 German control subjects. TH
variants were not associated with suicide (uncorrected P ¼ 0.023) and related traits. Some marginal
associations could be observed for DDC with
suicide, violence, anger, and aggression. In conclusion, our study does not support the involvement of TH gene variants as major contributors to
suicide, whereas DDC variants could mediate
some features related to suicide and be involved
in violent suicidal behavior. ß 2007 Wiley-Liss, Inc.
KEY WORDS: suicide; tyrosine hydroxylase;
dopa decarboxylase; genetics;
dopamine synthesis
Please cite this article as follows: Giegling I, MorenoDe-Luca D, Rujescu D, Schneider B, Hartmann AM,
Schnabel A, Maurer K, Möller H-J, Serretti A. 2008. Dopa
Decarboxylase and Tyrosine Hydroxylase Gene Variants in Suicidal Behavior. Am J Med Genet Part B
147B:308–315.
INTRODUCTION
Being one of the main causes of death in young people and
psychiatric patients [Statham et al., 1998; Birt et al., 2003],
suicidal behavior is a major public health issue. There is
a genetic component in suicidal behavior and its heritability
has been estimated to be above 40% [McGuffin et al., 2001;
*Correspondence to: Alessandro Serretti, M.D., Institute of
Psychiatry, University of Bologna, Viale Carlo Pepoli 5, 40123
Bologna, Italy. E-mail: alessandro.serretti@unibo.it
**Correspondence to: Dan Rujescu, M.D., Molecular and
Clinical Neurobiology, Department of Psychiatry, LudwigMaximilians-University, Nussbaumstr. 7, D-80336 Munich, Germany. E-mail: Dan.Rujescu@med.uni-muenchen.de
Received 22 January 2007; Accepted 21 June 2007
DOI 10.1002/ajmg.b.30599
ß 2007 Wiley-Liss, Inc.
Brent and Mann, 2005]. Progress has been made, leading to the
identification of gene variants in the serotoninergic system
associated to suicidal behavior, but given the complex nature
of the condition, and the probability of multiple interacting
systems, other pathways need to be considered [Mann, 2003;
Van Heeringen and Marusic, 2003; Rujescu et al., 2007].
Components of the dopaminergic system has been previously
associated to suicidal behaviors [Oquendo and Mann, 2000;
Rujescu et al., 2003; Ryding et al., 2006] and aggression regulation [Pitchot et al., 2001a,b; Rujescu et al., 2003], hence
making the pathway a good candidate to be studied in this
condition. Dopamine is synthesized from the amino acid
tyrosine undergoing two steps, the first producing DOPA by
Tyrosine Hydroxylase (TH) and the second from DOPA to
dopamine by the DOPA decarboxylase (DDC). Both steps
could therefore modulate the system. Low concentrations of
homovanillic acid, a metabolite produced by the catabolism
of dopamine, have been found in cerebrospinal fluid of depressed patients which attempted suicide compared to controls
[Engstrom et al., 1999], supporting the hypothesis of a
diminished dopaminergic neurotransmission in suicidal
behavior [Roy et al., 1992], though not unequivocally [Asberg,
1997]. Furthermore, Immunoglubulin G (IgG) with affinity for
dopamine has been found augmented in the cerebrospinal fluid
of suicide attempters compared to controls, proposing an
autoimmune approach to the aetiology of suicide but again
suggesting the pathophysiological importance of the dopaminergic system in this behavior [Bergquist et al., 2002]. Finally,
DDC is also involved in the serotonin pathway through
5-hydroxytryptophan decarboxylation [Boadle-Biber, 1993].
TH is located on chromosome 11p15, contains 13 exons, and
spans approximately 8 kb. It encodes for four alternatively
spliced transcripts, two of which (both lacking exon 2) are
expressed in the brain [O’Malley et al., 1987; Persson et al.,
1997]. Imunohistochemical evidence for differences in TH
expression in the locus coeruleus of suicide victims compared to
controls has been presented, and genetic differences have been
postulated as an explanation [Souery et al., 2003]. However,
the reported findings are conflicting, showing decreased
[Biegon and Fieldust, 1992] and increased [Ordway et al.,
1994] levels. A functional penta-allelic tetranucleotide polymorphism in the TH gene has been described beginning at base
pair (bp) 1,170 in intron 1 [Polymeropoulos et al., 1991; Meloni
et al., 1998] and the TH—K3 allele (252 bp) has been found
to have a higher prevalence among suicide victims, as opposed
to the TH—K1 allele (260 bp), more rarely found in the group
[Persson et al., 1997].
DDC is located on chromosome 7p11-p12.1, and consists of
15 exons spanning more than 100 kb [Sumi-Ichinose et al.,
1992]. DDC gene variants have not been investigated in
relation to suicide-related behaviors or phenotypes.
Several lines of evidence indicate that dopaminergic neurotransmission is involved in the regulation of impulsive
aggression and violence and that genetically determined
DDC and TH Gene Variants in Suicide
variability in dopaminergic gene expression modifies aggression-related behaviors [Retz et al., 2003; Chen et al., 2005]. The
strong association between aggression and suicide-related
behaviors [Rujescu et al., 2003; Baud, 2005; Bronisch et al.,
2005; Turecki, 2005; Dumais et al., 2005a,b] leads to the need of
including aggression measurements as intermediate phenotypes.
Due to the insufficient or heterogeneous findings reported up
to date, and backed up by the biological plausibility comprising
the involvement of the dopaminergic pathway in suicide, we
decided to investigate a set of markers in the DDC (rs1451371,
rs1470750, rs998850), and TH (rs3842727, rs6356) genes in
167 suicide attempters, 92 suicide completers, and 312 healthy
subjects.
MATERIALS AND METHODS
Patients
The recruitment of suicide attempters was carried out
among patients consecutively referred to general psychiatric
wards of the Department of Psychiatry, Ludwig-MaximiliansUniversity, Munich. The sample has been published for
investigations on other gene variants [Rujescu et al., 2001;
Serretti et al., 2007]. Systematic information on suicide
attempts was collected by repeated interviews with the
patients, all available medical records, and the Basic Documentation for Suicidal Behavior [Kulessa et al., 1987], in
order to discriminate between suicide attempts and other
forms of self-harming behaviors, accidents etc. Only patients of
German descent (i.e., both parents were German) with at least
one clear-cut suicide attempt were included.
Suicide attempts were classified as violent (hanging, stabbing, shooting, jump from buildings or in front of vehicles,
severe deliberate car accident, electricity, fire) or non-violent
(illicit or prescription drugs, wrist manipulations, gas suffocation, drowning) according to the method used and the severity
of the attempt. Patients who had a prior violent suicide attempt
were classified as violent regardless of the method used for the
most recent attempt.
The German version of the Intent Score Scale [Pierce, 1981]
was also used to define impulsive and non-impulsive suicidal
behavior. If the patient manifested not having had suiciderelated thoughts before the attempt, the impulsive attempt
was classified as spontaneous. Current and lifetime diagnoses
of mental disorders were assessed close to discharge by
applying the SCID I interview [First et al., 1995]. Patients
with severe general medical condition or with dementia were
309
excluded. 167 suicide attempters (58 males and 109 females)
were included in the study. Their mean age was 39.89 13.89
(range: 18–73) years. The suicide attempts of 60 patients were
classified as violent and of 101 as impulsive. DSM-IV lifetime
diagnoses of mental disorders among the patients were as
follows: affective spectrum (n ¼ 107, 64.07%), schizophrenia
spectrum (n ¼ 35, 20.96%) and borderline personality disorder
(n ¼ 25, 14.97%).
Given previous reports of association between aggressionrelated behaviors and suicide risk [Dumais et al., 2005a;
Turecki, 2005] and markers associated with those traits
[Rujescu et al., 2003], we also collected this information.
Patients and controls were further characterized with the
State-Trait Anger Expression Inventory (STAXI) [Spielberger,
1991]. The instrument consists of seven subscales: State Anger,
Trait Anger, Angry Temperament, Angry Reaction, Anger-In,
Anger-Out, and Anger Control. A total score was computed for
each subscale. Furthermore, we used the Questionnaire for
Measuring Factors of Aggression (FAF) [Hampel and Selg,
1975] which is a German analog of the German Buss and Durkee
Hostility Inventory—BDHI [Buss and Durkee, 1957]—and
evaluates various components of aggressive behavior: ‘‘Spontaneous Aggression’’ that comprises thoughts about being verbally
or physically aggressive towards other people, ‘‘Reactive
Aggression’’ that describes thoughts, and acts of assaults,
‘‘Irritability’’ that measures the tendency to get easily frustrated
and the lack of control on emotions, ‘‘Self-Aggression’’ that is
related with resentments, suspicion, and depressive thoughts,
‘‘Aggression Inhibition’’ that measures the possibility to control
aggressive acts, and thoughts, ‘‘Openness’’ that gives evidence
for the honesty and openness, and ‘‘Aggression’’ that is a sum
score comprising the items ‘‘Spontaneous Aggression,’’ ‘‘Reactive Aggression’’ and ‘‘Irritability.’’
The post-mortem sample consisted of 92 Caucasian individuals (53 males and 39 females) who committed suicide.
The individuals were recruited at the Institute of Forensic
Medicine, Johann Wolfgang Goethe-University, Frankfurt/
Main, Germany, after approval by the institutional Ethics
Committee. The mean age was 51.8 18.5 (range: 19–86) years.
Controls
Unrelated volunteers of German descent (i.e., both parents
German) were randomly selected from the general population
of Munich, Germany, and contacted by mail. To include only
subjects without personal or family history of neuropsychiatric
TABLE I. TH Single Markers and Suicide
rs3842727
Genotypes
Controls
Cases
Alleles
A/A
A/C
C/C
141 (45.19%)
138 (53.28%)
136 (43.59%)
103 (39.77%)
(w ¼ 5.23, df ¼ 2, P ¼ 0.073)
35 (11.22%)
18 (6.95%)
2
A
C
418 (66.99%)
206 (33.01%)
379 (73.17%)
139 (26.83%)
2
(w ¼ 5.15, df ¼ 1, P ¼ 0.023)
rs6356
Genotypes
Controls
Cases
Alleles
A/A
A/G
G/G
43 (13.83%)
30 (11.63%)
133 (42.77%)
123 (47.67%)
(w2 ¼ 1.53, df ¼ 2, P ¼ 0.46)
135 (43.41%)
105 (40.70%)
No significant association was observed.
A
G
219 (35.21%)
403 (64.79%)
183 (35.47%)
333 (64.53%)
(w2¼0.01, df ¼ 1, P ¼ 0.93)
P ¼ 0.76
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P ¼ 0.13
P ¼ 0.68
P ¼ 0.84
P ¼ 0.62
P ¼ 0.30
P ¼ 0.46
P ¼ 0.03
P ¼ 0.65
P ¼ 0.71
P ¼ 0.27
Table shows the P-values of the effect of polymorphisms, age, and education.
P ¼ 1.00
P ¼ 1.00
P ¼ 0.55
P ¼ 0.20
P ¼ 0.44
P ¼ 0.37
P ¼ 0.37
P ¼ 0.12
P ¼ 0.40
P ¼ 0.60
P ¼ 0.27
P ¼ 0.10
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P < 0.001
P ¼ 0.05
P ¼ 0.06
P ¼ 0.07
P ¼ 0.56
P ¼ 0.42
P ¼ 0.41
P ¼ 0.33
P ¼ 0.02
P ¼ 0.05
P ¼ 0.19
P ¼ 0.39
P ¼ 0.42
P ¼ 0.48
P ¼ 0.21
P ¼ 0.34
P ¼ 0.48
P ¼ 0.72
P ¼ 0.68
P ¼ 0.42
P ¼ 0.12
P ¼ 0.56
P ¼ 0.96
P ¼ 0.43
P ¼ 0.22
P ¼ 0.37
P ¼ 0.95
P ¼ 0.44
P ¼ 0.15
P ¼ 0.12
P ¼ 0.35
P ¼ 0.54
P < 0.001
P ¼ 0.40
P ¼ 0.19
P ¼ 0.64
P ¼ 0.30
P ¼ 0.01
P ¼ 0.004
P ¼ 0.09
P ¼ 0.14
P ¼ 0.30
P ¼ 0.12
P ¼ 0.005
P ¼ 0.99
P < 0.001
P ¼ 0.46
P ¼ 0.55
P ¼ 0.92
P ¼ 0.41
P ¼ 0.79
P ¼ 0.65
P ¼ 0.45
P ¼ 0.44
P ¼ 0.21
P ¼ 0.36
P ¼ 0.23
P ¼ 0.33
P ¼ 0.006
P ¼ 0.42
P ¼ 0.11
P ¼ 0.12
P ¼ 0.34
P ¼ 0.09
P ¼ 0.76
P ¼ 0.30
P ¼ 0.43
P ¼ 0.14
P ¼ 0.41
P ¼ 0.69
P ¼ 0.33
P ¼ 0.50
P ¼ 0.25
P ¼ 0.77
P ¼ 0.36
P ¼ 0.61
P ¼ 0.42
P ¼ 0.88
P ¼ 0.93
P ¼ 0.29
P ¼ 0.83
P ¼ 0.49
P ¼ 0.86
P ¼ 0.84
P ¼ 0.92
P ¼ 0.67
P ¼ 0.83
P ¼ 0.95
P ¼ 0.13
P ¼ 0.17
P ¼ 0.18
P ¼ 0.27
P ¼ 0.84
P ¼ 0.67
P ¼ 0.11
STAXI sub-scales
State anger
Trait anger
Angry temperament
Angry reaction
Anger in
Anger out
Anger control
FAF sub-scales
Spontaneous aggression
Reactive aggression
Irritability
Self aggression depression
Aggression inhibition
Openness
Aggression
Age
Haplotypes
rs998850
rs1470750
rs1451371
Haplotypes
rs6356
Statistical Analyses
The comparison of sociodemographic parameters between
the tested groups was made through w2- and T-tests. Using the
w2-test for independence, the genotype, and allele distributions
were compared between the suicide attempters, suicide
completers, and controls. Subgroups of suicide attempters
were also compared with controls in terms of genotype and
allele distributions. The linkage disequilibrium map and
the assessment of the Hardy–Weinberg equilibrium were
performed using Haploview 3.2 [Barrett et al., 2005]. To
compare the STAXI and FAF scores for each SNP, separate
three factor multivariate analysis of variance (MANCOVA)
was computed for controls and suicide attempters integrating
the seven subscales of the STAXI (or the 7 subscales of the FAF)
as well as the three factors: genotype, gender (males, females)
and diagnosis (healthy volunteers, suicide attempters) controlled for the covariates age and educational level (low,
middle, high). MANOVA was followed by univariate analysis.
We used the statistics environment ‘‘R’’ (http://www.R-project.
org), package ‘‘haplo.score’’ for haplotype analyses and to
compare STAXI and FAF scores between haplotypes. Sex,
age, education, and diagnosis were added as covariates. The
expectation-maximization algorithm infers haplotypes and
calculates maximum-likelihood frequency estimates. Single
haplotype significance and odds ratios were calculated as
well as global significance. Permutation (10,000 permutations)
was also performed to estimate the global significance of
rs3842727
TH rs3842727, rs6356, and DDC rs1451371, rs1470750,
rs998850 were genotyped by Illumina (Illumina, Inc, San
Diego) through use of their Integrated BeadArray System.
Additionally, 23 SNPs in genes spanning all chromosomes
were genotyped as genomic controls (rs2006727; rs586726;
rs724529; rs206847; rs1868155; rs2009602; rs1383628;
rs876635; rs1367828; rs2076940; rs2025557; rs1993181;
rs2168213; rs948184; rs2227973; rs1713449; rs2295152;
rs1800404; rs1469122; rs731835; rs418251; rs725493;
rs1555048). These genes have been selected based on the low
a priori probability of involvement in behavioral traits and
phenotypes. We supplied Illumina with barcoded DNA microliter plates containing the DNA quantified with Pico Green to
be at 100 ng/ml and Illumina delivered genotypes with a quality
score calculated by proprietary Illumina algorithms.
DDC polymorphisms
Genotyping
TH polymorphisms
disorders, a screening was performed before enrolment in the
study. First, subjects who responded were initially screened by
phone. Detailed medical and psychiatric histories were
assessed for both themselves and their first-degree relatives
by using systematic forms. Second, they were invited to a
comprehensive interview including the Structured Clinical
Interview for DSM-IV (SCID I and SCID II) [First et al., 1990,
1995] to evaluate their lifetime Axis I and II disorders.
Psychiatric diagnoses among their first-degree relatives
were assessed using the Family History Assessment Module
[Rice et al., 1995]. Subjects with relevant somatic diseases or a
lifetime history of any Axis I or II psychiatric disorders or
suicidal behavior were excluded. Subjects who had first-degree
relatives with a lifetime history of a mental disorder or suicidal
behavior were also excluded. Finally, 312 control subjects (138
males and 174 females) were included. Their mean age was
45.01 14.92 (range: 19–79) years.
Written informed consent was obtained from all subjects
after a detailed and extensive description of the study, which
was approved by the local ethics committee, and carried out in
accordance to the ethical standards laid down in the Declaration of Helsinki.
Education
Giegling et al.
TABLE II. Multivariate Analysis for DDC and TH Alleles on STAXI and FAF Sub-scales; Age and Education Were Included as Covariates
310
DDC and TH Gene Variants in Suicide
311
TABLE III. TH Haplotype Frequencies and Suicide
Haplotype
Controls
Cases
Stat.
P
OR
0.011
0.319
0.341
0.329
0.0
0.268
0.355
0.377
2.08
1.98
0.38
1.86
0.038
0.048
0.703
0.063
0.001
0.728
0.899
1.00
C-A
C-G
A-A
A-G
Marginal association was observed.
the results for haplotype analyses to validate the EM
values.
We conservatively calculated the power of our sample
with an alpha level of 0.005. For single marker analyses in
our sample we had a power of 0.80 to detect a small effect size
of w ¼ 0.156 that corresponded to a difference of approximately
15% between two genotypes (OR ¼ 1.86) [Cohen, 1988]. For
haplotype analyses, considering a frequency of the disease
allele of 0.3, disease prevalence of 0.01, phenocopy rate of
0.1, penetrance of 0.8, a codominant transmission model,
strong LD (D-prime ¼ 0.8) between disease and marker; we
had sufficient power (0.80) to detect a genotypic relative risk of
1.57 (Aa) and 2.48 (AA) [Purcell and Sham, 2001; Purcell
et al., 2003].
RESULTS
Gender rates were similar among controls and suicide
attempters/completers (females in controls vs. cases: 55.7%
vs. 57.4%, w2 ¼ 0.15, df ¼ 1, P ¼ 0.70), though a small excess of
females in suicide attempters compared to controls was
observed (w2 ¼ 4.10, df ¼ 1, P ¼ 0.043). Significant differences
were observed in age (controls vs. cases: 45.1 14.9 vs.
39.9 13.9, t ¼ 3.7, df ¼ 477, P ¼ 0.0002) as well as in educational level (controls vs. cases: 2.18 0.82 vs. 1.96 0.79,
Z ¼ 2.84, P ¼ 0.0045), leading us to control results for age,
education, and sex. We also systematically controlled for these
variables and for diagnosis (control/suicide attempter) when
analyzing FAF and STAXI scores in relation to genotypes and
haplotypes. As expected, none of the 23 SNPs in the genomic
control genes showed an association with suicidal behavior
(data not shown).
Tyrosine Hydroxylase
Markers were in Hardy–Weinberg equilibrium (rs3842727:
P ¼ 0.92, rs6356: P ¼ 0.77) and in strong linkage disequilibrium
both in patients (D0 ¼ 0.90) and controls (D0 ¼ 1.0). Singlemarker analyses revealed no association with rs6356, while
rs3842727 showed a trend for association with suicidal behavior
(Table I), with the A allele observed more frequently in suicidal
patients than in controls, but without reaching statistical
significance uncorrected P ¼ 0.023. No significant effects at the
single-marker level were observed in relation to completed
versus attempted (rs3842727: P ¼ 0.07, rs6356: P ¼ 0.77), violent
versus non-violent (rs3842727: P ¼ 0.42, rs6356: P ¼ 0.47),
impulsive versus non-impulsive (rs3842727: P ¼ 0.67, rs6356:
P ¼ 0.28) suicidal behavior. Furthemore, TH markers were not
associated with STAXI and FAF scores (Table II).
TH haplotypes did not show significant associations with
suicidal behavior, though a marginal trend (Global Stat. ¼
8.81, df ¼ 3, P ¼ 0.032) toward a protective effect of the C-A
haplotype was observed. However, the observed (Table III)
significance was very low and permutation analysis did not
confirm the finding (Max-sim P ¼ 0.13), thus suggesting an
effect driven by rs3842727 only. Haplotypes did not seem to
TABLE IV. DDC Single Markers and Suicide
rs1451371
Genotypes
T/T
Controls
Cases
T/C
Alleles
C/C
105 (33.65%)
130 (41.67%)
77 (24.68%)
68 (26.25%)
137 (52.90%)
54 (20.85%)
(w2 ¼ 7.29, df ¼ 2, P ¼ 0.03)
T
C
340 (54.49%)
284 (45.51%)
273 (52.70%)
245 (47.30%)
(w2 ¼ 0.36, df ¼ 1, P ¼ 0.55)
rs1470750
Genotypes
G/G
Controls
Cases
G/C
Alleles
C/C
115 (36.86%)
131 (41.99%)
66 (21.15%)
87 (33.59%)
124 (47.88%)
48 (18.53%)
2
(w ¼ 2.01, df ¼ 2, P ¼ 0.36)
G
C
263 (42.15%)
361 (57.85%)
220 (42.47%)
298 (57.53%)
2
(w ¼ 0.01, df ¼ 1, P ¼ 0.91)
rs998850
Genotypes
C/C
Controls
Cases
C/G
Alleles
G/G
76 (24.36%)
134 (42.95%)
102 (32.69%)
52 (20.23%)
130 (50.58%)
75 (29.18%)
(w2 ¼ 3.40, df ¼ 2, P ¼ 0.18)
Marginal association was observed.
C
G
286 (45.83%)
338 (54.17%)
234 (45.53%)
280 (54.47%)
(w2 ¼ 0.01, df ¼ 1, P ¼ 0.92)
312
Giegling et al.
TABLE V. DDC Haplotype Frequencies and Suicide
Haplotypes
T-G-C
C-C-G
T-G-G
C-G-G
C-G-C
T-C-G
C-C-C
Controls
Cases
Stat.
P
OR
0.4
0.4
0.08
0.04
0.01
0.02
0.002
0.4
0.4
0.09
0.03
0.02
0.006
0.002
0.19
0.13
0.18
0.16
1.64
2.70
0.03
0.66
0.72
0.67
0.69
0.20
0.10
0.87
1.32
1.27
1.37
1.19
2.50
1.62
1.0
No association was observed.
exert a significant influence on completed versus attempted
(P ¼ 0.45), violent versus non-violent (P ¼ 0.51), impulsive
versus non-impulsive (P ¼ 0.19) suicidal behaviors. Haplotype
analyses did not show significant effects of TH variants on
STAXI and FAF scores.
DOPA Decarboxylase
Hardy-Weinberg equilibrium was observed in the whole
sample (rs1451371: P ¼ 0.17, rs1470750: P ¼ 0.05, rs998850:
P ¼ 0.14), as well as in suicide attempters/completers
(rs1451371: P ¼ 0.41, rs1470750: P ¼ 0.82, rs998850: P ¼ 0.87)
and in controls (rs1451371: P ¼ 0.15, rs1470750: P ¼ 0.04,
rs998850: P ¼ 0.12). Markers were in strong LD, both in the
whole sample (rs1451371-rs1470750: D0 ¼ 0.94; rs1451371rs998850: D0 ¼ 0.91; rs1470750-rs998850: D0 ¼ 0.99), in controls and suicide attempters/completers.
Genotypes were not associated with suicidal behavior,
except for a minor excess of the rs1451371*T/C genotype in
cases (Table IV); no significant difference was observed
between suicide attempters, and completers (data not shown
in tables: rs1451371: P ¼ 0.27; rs1470750: P ¼ 0.47; rs998850:
P ¼ 0.69). Haplotype analysis did not yield any significant
association (global P ¼ 0.56) (Table V). As well, haplotypes
were not associated with completed versus attempted suicide
(Global P ¼ 0.83).
Among suicide attempters, rs1451371 and rs1470750
showed a trend to be associated with non-violent suicide
methods (Table VI). Haplotypes were instead not associated
with violent attempts (Global Stat. ¼ 9.11, df ¼ 6, P ¼ 0.17),
except for a marginal effect exerted by the C-C-G haplotype
(Freq. ¼ 0.40, Stat. ¼ 2.01, P ¼ 0.04). Sliding windows analysis revealed a partial effect of rs1451371 and rs1470750, with
the C-C haplotype more frequent among non-violent suicide
attempters (Global Stat. ¼ 7.70, df ¼ 3, P ¼ 0.05; haplotype
T-G: freq. ¼ 0.54 Stat. ¼ 2.44, P ¼ 0.015).
The DDC SNPs were not associated with impulsive suicide attempts, neither as single markers (rs1451371: w2 ¼
0.06, df ¼ 1, P ¼ 0.81, rs1470750: w2 ¼ 0.01, df ¼ 1, P ¼ 0.92,
rs998850: w2 ¼ 0.02, df ¼ 1, P ¼ 0.88) nor as haplotypes (Global
Stat. ¼ 0.95, df ¼ 5, P ¼ 0.97).
However, rs998850 showed small but positive allelic association with anger (STAXI Anger Out) and aggressive scores
(FAF Spontaneous aggression, Reactive Aggression and
Aggression) (Table II). In Table VII we reported rs998850
mean values for genotypes, the finding was marginally
confirmed for STAXI Anger Out.
DISCUSSION
In the present article we found no major association between
TH gene variants and suicide-related behavior, except for a
small excess of the rs3842727*A allele in cases. Our findings
are convergent with previous negative results [Korner et al.,
1994], but not with others [Persson et al., 1997], although no
direct comparison can be made because the gene areas we
TABLE VI. DDC Single Markers and Violence of Suicide Attempt
rs1451371
Suicide Method
T/T
%
T/C
%
C/C
%
Non-violent
Violent
24
22
22.43
36.67
58
32
54.21
53.33
24
6
23.36
10.00
(w2 ¼ 6.8, df ¼ 2, P ¼ 0.03)
rs1470750
Non-violent
Violent
G/G
%
G/C
%
C/C
%
33
24
30.84
40.00
52
30
48.60
50.00
22
6
20.56
10.00
G/G
%
32
15
30.48
25.00
(w2 ¼ 6.81, df ¼ 2, P ¼ 0.038)
rs998850
Non-violent
Violent
C/C
%
18
18
17.14
30.00
Marginal association was observed.
C/G
%
55
52.38
27
45.00
(w2 ¼ 3.62, df ¼ 2, P ¼ 0.16)
DDC and TH Gene Variants in Suicide
313
TABLE VII. Mean Scores for State-Trait Anger Expression Inventory (STAXI) and Factors of Aggression (FAF) Subscales as a
Function of DDC rs998850 Genotype (STAXI: df ¼ 2,412; FAF: df ¼ 2,409)
rs998850 genotype
STAXI sub-scales
State anger
Trait anger
Angry temperament
Angry reaction
Anger in
Anger out
Anger control
FAF sub-scales
Spontaneous aggression
Reactive aggression
Irritability
Self aggression depression
Aggression inhibition
Openness
Aggression
G/G (n ¼ 129)
C/G (n ¼ 184)
C/C (n ¼ 102)
Mean SD
12.19 3.96
17.31 4.43
7.62 2.06
9.68 2.99
16.26 5.28
12.27 3.61
24.25 4.50
Mean SD
12.42 4.77
17.34 4.91
7.56 2.40
9.78 3.07
16.13 5.22
11.77 3.52
24.26 4.71
Mean SD
12.15 3.72
16.53 4.83
7.41 2.41
9.12 3.11
16.34 5.52
11.65 3.49
24.87 4.68
F
0.11
2.15
0.86
2.54
0.69
5.39
0.84
P
0.73
0.14
0.35
0.35
0.41
0.020
0.36
21.33 3.36
15.89 2.92
17.23 2.75
14.04 3.13
15.81 2.22
14.80 2.06
54.46 7.77
21.15 2.96
15.78 2.68
17.01 2.84
14.08 3.17
15.68 2.28
15.01 1.92
53.95 7.14
21.34 3.22
15.63 2.41
16.78 2.93
14.02 3.33
15.73 2.08
14.71 2.08
53.75 7.45
0.04
0.32
3.12
0.01
0.14
0.05
0.95
0.83
0.60
0.078
0.92
0.71
0.82
0.33
explored do not comprise the intron 1 polymorphism previously
studied [Polymeropoulos et al., 1991]. With rs3842727 being
located in the 30 UTR and rs6356 in the third exon, more than
6 kbs away, we consider to have covered a wide region of the
gene, as confirmed by the strong linkage disequilibrium
observed among the SNPs.
The trend of association we observed between suicide and
rs3842727 could be congruent with previous reports of differences in immunohystochemical brain TH concentrations
[Souery et al., 2003]. Although one could speculate that mRNA
stability may be affected, since the marker is in the 30 UTR,
little is known about its functionality, and no support for either
augmented or decreased levels can be inferred. It has been
suggested to implement intermediate phenotypes in gene
discovery [Meyer-Lindenberg and Weinberger, 2006] but with
regard to the aggression-and anger-related phenotypes investigated in this study, no major association was observed either.
The negative results are preserved when analyzing sub-groups
stratified for violence, impulsiveness, completion versus attempt [Rujescu et al., 2003].
Both SNPs are in the promoter region of the insulin gene as
well, although some studies have shown the involvement of
that gene in suicidal behavior [Golomb et al., 2002; Westling
et al., 2004] our negative results do not support this view.
Some marginal association with suicide was found regarding
the DDC gene; this is the first time this gene has been reported
in suicidal behavior. A trend of association with non-violent
methods was seen for rs1451371 and rs1470750. Furthermore,
DDC was mildly associated with some measures of anger and
aggression. This is in line with evidences linking aggression to
the dopaminergic system.
Our study does not lack limitations: neither the promoter nor
the 50 region of the TH gene were covered, taking into account
that prior findings in suicidal behavior reported association
with this region [Persson et al., 1997]. The promoter and the
50 region of the gene were not investigated in the DDC gene and
the variants previously studied were all intronic, resulting in
findings based in non-coding sequences only.
Another possible bias is the fact that controls might commit
or attempt suicide in the future. However, we used screened
controls to minimize this issue [Moskvina et al., 2005]. The
research hypothesis was to investigate liability genes for
suicidal behavior, this could be biased by the fact that suicidal
subjects were also affected by psychiatric disturbances,
however the heritability of suicide has been suggested to be
independent from psychiatric diagnosis [McGuffin et al., 2001;
Brent and Mann, 2005], and consideration of psychiatric
diagnosis did not influence our observed results. Ethnic origin
is also a frequent cause of stratification bias, but our sample
was composed of subjects from Germany with local antecedents
for at least two generations. Completers are of Caucasian
descent. The German population is considered to be genetically
homogeneous [Cavalli Sforza, 1994] and the genomic control
SNPs [Pritchard and Rosenberg, 1999] confirmed this hypothesis. The power of the present study, also considering a quite
conservative alpha level of 0.005, was sufficient enough to
detect ORs of 1.86, which is in the risk range caused by minor
effect genes [Kendler, 2005]. Nevertheless, smaller effects
could have been missed, as an example OR ¼ 1.5 could be
detected with a 0.34 power, and OR ¼ 1.2 with a negligible 0.05.
Moreover the large number of comparisons may lead to Type I
errors (cases vs. controls, victims vs. attempts, aggression,
anger, violence, impulsivity, haplotypes). Also the use of haplotypes in case-control studies has been questioned [Curtis and
Sham, 2006], but our mainly negative findings do not pose the
risk of a false positive result. The analysis of continuous
measures of anger and aggression could have been biased by
the bimodal distribution of the scores between patients and
controls, however the use of diagnosis as main factor could
reduce this bias. Finally, a number of factors other than
hereditary, which are quite difficult to include in research
studies, affect suicidal behavior [Gunnell and Lewis, 2005;
McKenzie et al., 2005].
In conclusion, our study does not support a major involvement of TH gene variants in suicide-related behavior, however
the DDC gene may play a role, potentially mediating anger,
and aggressive traits.
REFERENCES
Asberg M. 1997. Neurotransmitters and suicidal behavior. The evidence
from cerebrospinal fluid studies. Ann NY Acad Sci 836:158–181.
Barrett JC, Fry B, Maller J, Daly MJ. 2005. Haploview: Analysis and
visualization of LD and haplotype maps. Bioinformatics 21:263–
265.
Baud P. 2005. Personality traits as intermediary phenotypes in suicidal
behavior: Genetic issues. Am J Med Genet Part C 133C:34–42.
314
Giegling et al.
Bergquist J, Traskman-Bendz L, Lindstrom MB, Ekman R. 2002.
Suicide-attempters having immunoglobulin G with affinity for dopamine in cerebrospinal fluid. Eur Neuropsychopharmacol 12:153–
158.
Biegon A, Fieldust S. 1992. Reduced tyrosine hydroxylase immunoreactivity
in locus coeruleus of suicide victims. Synapse 10:79–82.
Birt C, Bille-Brahe U, Cabecadas M, Chishti P, Corcoran P, Elgie R, van
Heeringen K, Horte L-G, Marchi AG, Ostamo A, Petridou E, Renberg ES,
Stone DH, Wiik J, Williamson E. 2003. Suicide mortality in the
European Union. Eur J Public Health 13:108–114.
Boadle-Biber MC. 1993. Regulation of serotonin synthesis. Prog Biophys
Mol Biol 60:1–15.
Brent DA, Mann JJ. 2005. Family genetic studies, suicide, and suicidal
behavior. Am J Med Genet Part C 133C:13–24.
Bronisch T, Brunner J, Bondy B, Rujescu D, Bishof G, Heuser I, MullerOerlinghausen B, Hawellek B, Maier W, Rao ML, Felber W, Lewitzka U,
Oehler J, Broocks A, Hohagen F, Lauterbach E. 2005. A multicenter
study about Neurobiology of Suicidal Behavior: Design, development,
and preliminary results. Arch Suicide Res 9:19–26.
Mann JJ. 2003. Neurobiology of suicidal behaviour. Nat Rev Neurosci
4:819–828.
McGuffin P, Marusic A, Farmer A. 2001a. What can psychiatric genetics
offer suicidology? Crisis 22:61–65.
McKenzie N, Landau S, Kapur N, Meehan J, Robinson J, Bickley H, Parsons
R, Appleby L. 2005. Clustering of suicides among people with mental
illness. Br J Psychiatry 187:476–480.
Meloni R, Albanese V, Ravassard P, Treilhou F, Mallet J. 1998. A
tetranucleotide polymorphic microsatellite, located in the first intron
of the tyrosine hydroxylase gene, acts as a transcription regulatory
element in vitro. Hum Mol Genet 7:423–428.
Meyer-Lindenberg A, Weinberger D. 2006. Intermediate phenotypes and
genetic mechanisms of psychiatric disorders. Nat Rev Neurosci 7(10):
818–827.
Moskvina V, Holmans P, Schmidt KM, Craddock N. 2005. Design of casecontrols studies with unscreened controls. Ann Hum Genet 69:566–
576.
Buss AH, Durkee A. 1957. An inventory for assessing different kinds of
hostility. J Consult Psychol 21:343–349.
O’Malley KL, Anhalt MJ, Martin BM, Kelsoe JR, Winfield SL, Ginns EI.
1987. Isolation and characterization of the human tyrosine hydroxylase
gene: Identification of 50 alternative splice sites responsible for multiple
mRNAs. Biochemistry 26:6910–6914.
Cavalli Sforza L. 1994. The History and Geography of Human Genes.
Princeton, New Jersey, USA: Princeton University Press.
Oquendo MA, Mann JJ. 2000. The biology of impulsivity and suicidality.
Psychiatr Clin North Am 23:11–25.
Chen TJ, Blum K, Mathews D, Fisher L, Schnautz N, Braverman
ER, Schoolfield J, Downs BW, Comings DE. 2005. Are dopaminergic
genes involved in a predisposition to pathological aggression? Hypothesizing the importance of ‘‘super normal controls’’ in psychiatricgenetic
research of complex behavioral disorders. Med Hypotheses 65:703–
707.
Ordway GA, Smith KS, Haycock JW. 1994. Elevated tyrosine hydroxylase in
the locus coeruleus of suicide victims. J Neurochem 62:680–685.
Cohen J. 1988. Statistical power analysis for the behavioral sciences.
Hillsdale, New Jersey: Lawrence Erlbaum Associates. pp 8–14.
Curtis D, Sham PC. 2006. Estimated haplotype counts from case-control
samples cannot be treated as observed counts. Am J Hum Genet 78:729–
730.
Dumais A, Lesage AD, Alda M, Rouleau G, Dumont M, Chawky N,
Roy M, Mann JJ, Benkelfat C, Turecki G. 2005a. Risk factors for
suicide completion in major depression: A case-control study of
impulsive and aggressive behaviors in men. Am J Psychiatry 162:
2116–2124.
Dumais A, Lesage AD, Lalovic A, Seguin M, Tousignant M, Chawky N,
Turecki G. 2005b. Is violent method of suicide a behavioral marker of
lifetime aggression? Am J Psychiatry 162:1375–1378.
Engstrom G, Alling C, Blennow K, Regnell G, Traskman-Bendz L. 1999.
Reduced cerebrospinal HVA concentrations and HVA/5-HIAA ratios in
suicide attempters. Monoamine metabolites in 120 suicide attempters
and 47 controls. Eur Neuropsychopharmacol 9:399–405.
First MB, Spitzer RL, Gibbon M, Williams BW, Benjamin L. 1990.
Structured Clinical Interview for DSM-IV Axis II Personality Disorders
(SCID-II). New York: Biometrics Research Department, New York State
Psychiatric Institute.
First MB, Spitzer RL, Gibbon M, Williams JB. 1995. Structured Clinical
Interview for DSM-IV Axis I Disorders—Patient Edition (SCID-I/P,
Version 2.0). New York: Biometrics Research Department, New York
State Psychiatric Institute.
Golomb BA, Tenkanen L, Alikoski T, Niskanen T, Manninen V, Huttunen M,
Mednick SA. 2002. Insulin sensitivity markers: Predictors of accidents
and suicides in Helsinki Heart Study screenees. J Clin Epidemiol
55:767–773.
Gunnell D, Lewis G. 2005. Studying suicide from the life course perspective:
Implications for prevention. Br J Psychiatry 187:206–208.
Hampel R, Selg H. 1975. FAF-Fragebogen zur Erfassung von Aggressivitätsfaktoren Hogrefe Verlag für Psychologie. Handanweisung, Gottingen
Kendler KS. 2005. ‘‘A gene for...’’: The nature of gene action in psychiatric
disorders. Am J Psychiatry 162:1243–1252.
Korner J, Rietschel M, Hunt N, Castle D, Gill M, Nothen MM, Craddock N,
Daniels J, Owen M, Fimmers R., et al. 1994. Association and haplotype
analysis at the tyrosine hydroxylase locus in a combined German-British
sample of manic depressive patients and controls. Psychiatr Genet
4:167–175.
Kulessa C, Möller H, Schaller S, Schmidtke A, Torhorst A, Wächtler C,
Wechsung P, Wedler H. 1987. Basisdokumentation suizidalen Verhaltens Hogrefe. Göttingen.
Persson ML, Wasserman D, Geijer T, Jonsson EG, Terenius L. 1997.
Tyrosine hydroxylase allelic distribution in suicide attempters. Psychiatry Res 72:73–80.
Pierce DW. 1981. The predictive validation of a suicide intent scale: A
five year follow-up. Br J Psychiatry 139:391–396.
Pitchot W, Hansenne M, Ansseau M. 2001a. Role of dopamine in nondepressed patients with a history of suicide attempts. Eur Psychiatry
16:424–427.
Pitchot W, Reggers J, Pinto E, Hansenne M, Fuchs S, Pirard S, Ansseau M.
2001b. Reduced dopaminergic activity in depressed suicides. Psychoneuroendocrinology 26:331–335.
Polymeropoulos MH, Xiao H, Rath DS, Merril CR. 1991. Tetranucleotide
repeat polymorphism at the human tyrosine hydroxylase gene (TH).
Nucleic Acids Res 19:3753.
Pritchard JK, Rosenberg NA. 1999. Use of unlinked genetic markers to
detect population stratification in association studies. Am J Hum Genet
65:220–228.
Purcell S, Sham P. 2001. Genetic Power Calculator. London: Social, Genetic
& Developmental Research Centre.
Purcell S, Cherny SS, Sham P. 2003. Genetic power calculator: Design of
linkage and association genetic mapping studies of complex traits.
Bioinformatics 19:149–150.
Retz W, Rosler M, Supprian T, Retz-Junginger P, Thome J. 2003. Dopamine
D3 receptor gene polymorphism and violent behavior: Relation to
impulsiveness and ADHD-related psychopathology. J Neural Transm
110:561–572.
Rice JP, Reich T, Bucholz KK, Neuman RJ, Fishman R, Rochberg N,
Hesselbrock VM, Nurnberger JI Jr, Schuckit MA, Begleiter H. 1995.
Comparison of direct interview and family history diagnoses of alcohol
dependence. Alcohol Clin Exp Res 19:1018–1023.
Roy A, Karoum F, Pollack S. 1992. Marked reduction in indexes of dopamine
metabolism among patients with depression who attempt suicide. Arch
Gen Psychiatry 49:447–450.
Rujescu D, Giegling I, Sato T, Moeller HJ. 2001. A polymorphism in the
promoter of the serotonin transporter gene is not associated with
suicidal behavior. Psychiatr Genet 11:169–172.
Rujescu D, Giegling I, Gietl A, Hartmann AM, Moller HJ. 2003. A functional
single nucleotide polymorphism (V158M) in the COMT gene is
associated with aggressive personality traits. Biol Psychiatry 54:34–
39.
Rujescu D, Thalmeier A, Moeller H-J, Bronisch T, Giegling I, 2007.
Molecular genetic findings in suicidal behavior; What is beyond the
serotonergic system? Arch Suicide Res 11:17–40.
Ryding E, Ahnlide JA, Lindstrom M, Rosen I, Traskman-Bendz L. 2006.
Regional brain serotonin and dopamine transporter binding capacity in
suicide attempters relate to impulsiveness and mental energy. Psychiatry Res 148:195–203.
DDC and TH Gene Variants in Suicide
Serretti A, Mandelli L, Giegling I, Schneider B, Hartmann AM, Schnabel A,
Maurer K, Moller HJ, Rujescu D. 2007. HTR2C and HTR1A gene
variants in German and Italian suicide attempters and completers. Am J
Med Genet B Neuropsychiatr Genet 144(3):291–299.
Souery D, Oswald P, Linkowski P, Mendlewicz J. 2003. Molecular genetics in
the analysis of suicide. Ann Med 35:191–196.
Spielberger C. 1991. State-Trait Anger Expression Inventory Assessment
Resources. Odessoa, FL: Psychological Assessment Resources.
Statham DJ, Heath AC, Madden PA, Bucholz KK, Bierut L, Dinwiddie SH,
Slutske WS, Dunne MP, Martin NG. 1998. Suicidal behaviour: An
epidemiological and genetic study. Psychol Med 28:839–855.
315
Sumi-Ichinose C, Ichinose H, Takahashi E, Hori T, Nagatsu T. 1992.
Molecular cloning of genomic DNA and chromosomal assignment of
the gene for human aromatic L-amino acid decarboxylase, the enzyme
for catecholamine and serotonin biosynthesis. Biochemistry 31:2229–
2238.
Turecki G. 2005. Dissecting the suicide phenotype: The role of impulsiveaggressive behaviours. J Psychiatry Neurosci 30:398–408.
Van Heeringen C, Marusic A. 2003. Understanding the suicidal brain. Br J
Psychiatry 183:282–284.
Westling S, Ahren B, Traskman-Bendz L, Westrin A. 2004. High CSFinsulin in violent suicide attempters. Psychiatry Res 129:249–255.
Документ
Категория
Без категории
Просмотров
3
Размер файла
91 Кб
Теги
suicidal, behavior, decarboxylase, dopa, hydroxylase, tyrosine, variant, genes
1/--страниц
Пожаловаться на содержимое документа