Molecular Psychiatry (2006) 11, 336–351

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FEATURE REVIEW

Genetics of suicide
B Bondy1, A Buettner2 and P Zill1
1
Section Psychiatric Genetics and Neurochemistry, Psychiatric Clinic, Ludwig-Maximilians-University, Munich, Germany
and 2Institute for Legal Medicine, Ludwig-Maximilians-University, Munich, Germany

The concept that genetic factors contribute to the complex trait of suicidal behaviour has
stimulated much work aimed at identifying susceptibility genes. So far molecular genetic
studies focused on the serotonergic pathway as the intent to die and the lethality of suicide
acts were related to the serotonergic system. Two genes have so far emerged as being
involved in the vulnerability for suicidality: first, the intronic polymorphisms (A218C or A779C)
of the tryptophan hydroxylase 1 (TPH1) gene, which was suggested as a quantitative risk
factor for suicidal behaviour; second, the insertion/deletion polymorphism of the serotonin
transporter gene (5-HTTLPR), which does not seem to be involved in general suicidal
behaviour, but in violent and repeated suicide attempts. The data have further shown that the
MAOA gene, which is consistently associated with impulsive-aggressive personality traits, is
not related to suicide but might induce violent methods in subjects with other suicide risk
factors. Predominantly negative were the findings with any type of the serotonin receptors
and inconsistent with catecholamine-synthesizing and -metabolizing enzymes or with the
dopaminergic receptors. This paper reviews the status of current knowledge in this area,
points to the weakness of the investigations and presents new approaches beyond the
serotonergic system.
Molecular Psychiatry (2006) 11, 336–351. doi:10.1038/sj.mp.4001803; published online 7 February 2006
Keywords: suicide; serotonin; genetics; polymorphism; association studies

Introduction areas.5 Several explanations have been considered for

Suicide is a significant public health issue and a
major cause of death throughout the world. Although
the epidemiological data vary from country to country
with the highest annual rates in a group of Eastern
European countries, which share similar historical
and socio-cultural characteristics, such as Estonia,
Latvia, Lithuania, Finland and Hungary and to a
lesser extent the Russian Federation; the WHO
estimates that suicide accounts for almost 2% of the
deaths in the world.1 There is a relatively consistent
predominance of completed suicide rates in males
over those in females with the exception of China,
where suicide rates are higher in females.2,3 Attemp-
ted suicide is more frequent than completed suicide
with a lifetime prevalence of about 3.5% and it is
usually estimated that up to 10% of suicide attemp-
ters will commit suicide within 10 years.4 Although
there is a clear tendency towards an increase in
suicide rates with age (for both men and women),
numerically more suicides are committed by younger
people and recent evidence suggests that suicide rates
of young people are increasing in many geographical
Correspondence: Professor Dr B Bondy, Section Psychiatric
Genetics and Neurochemistry, Psychiatric Clinic of University
Munich, Ludwig-Maximilians-University, Nussbaumstrasse 7,
Munich 80336, Germany.
E-mail: brigitta.bondy@med.uni-muenchen.de
Received 16 December 2005; accepted 22 December 2005;
published online 7 February 2006
national and regional variations, including climate,
religion, social and political systems, but a more
likely scenario is that the genetic contributions to
suicide will be represented by small size effects of
many gene variants associated with processes invol-
ved in suicidal behaviour, and by interaction of these
genetic factors with environmental factors.3,6
Defining the phenotype
Suicidal behaviour includes a wide spectrum and
refers to the occurrence of suicide attempts that range
from fatal acts (completed suicide) over highly lethal,
but failed suicide attempts (where high intention and
planning are evident and survival is fortuitous) to low
lethality, usually impulsive attempts triggered by a
social crisis which contain a strong element of an
appeal for help.7 Suicidal ideation, which comprises
suicidal thoughts or threats devoid of action, is more
common than suicide attempts and completed sui-
cide and its prevalence varies widely, being almost
twice in females compared to males. It was further
found that suicidal ideations are almost always
associated with a psychiatric disorder.8,9 Although
the exact clinical definition of suicidal behaviour
remains unsatisfactory and is a source of confusion,
the phenomenon of suicidality is often viewed as
occurring on a continuum of increasing severity from
ideation over attempts to completed suicide10 and

may be classified according to the intent to die,
method and lethality (violent or non-violent), cogni-
tive impairments (impulsivity, aggressiveness), or
mitigating circumstances.11 The method of suicide is
not randomly distributed. For example, violent
methods, assessed with a higher level of lifetime
aggression and a higher level of impulsivity, are more
often applied by males than by females. In addition,
violent methods were often associated with life-
time substance abuse or dependence and psychotic
disorders.12
Clinical correlates of suicidal behaviour
Several arguments suggest that suicidal behaviour is a
disorder on its own, although psychiatric distur-
bances are major contributing factors and about 90%
of suicide attempters have a psychiatric disorder
according to the Diagnostic and Statistical Manual of
Mental Disorder.7 The majority of all suicides occur in
relation to mood disorders, but also other psychiatric
disturbances such as schizophrenia, alcoholism and
drug abuse are similarly related to suicide5 (for review
see Mann13). Other clinical features that increase the
liability for suicidal behaviour include personality
traits, hopelessness, a history of physical or sexual
abuse during childhood, a history of head injury or
neurological disorder, and cigarette smoking.13,14
However, although the presence of a psychopathology
is a strong predictor for suicide, only a minority
of people with these diagnoses commit suicide. Thus,
a psychiatric diagnosis might be a necessary, but
insufficient, risk factor for suicide, indicating a
predisposition that is independent of the main
psychiatric disorders.13,15
Especially impulsive-aggressive traits, neuroticism
and anxiety-related traits, as well as anger-related
traits were proposed as intermediary phenotypes and
risk factors for suicidal behaviour.14 These traits seem
to be independent from the role of associated axis I
disorders, particularly major depression and may be
part of a developmental cascade that increases suicide
risk among a subset of patients.15 Further, as person-
ality traits themselves are partly under genetic
control, it was suggested that they may contribute to
the familial loading of suicide attempts and comple-
tions.14,15 On the other hand, it was proposed that
impulsive-aggressive personality disorders and alco-
hol abuse/dependence were two independent pre-
dictors of suicide in major depression, and impulsive
and depressive behaviours seem to underlie these risk
factors.12
Family studies in suicidal behaviour
It is long known that suicidal behaviour runs within
families and that this familial transmission cannot
solely be explained by the transmission of psychiatric
disorders alone, as the highest suicide rates were not
observed in the biological relatives of patients with
affective disorders, who by themselves have a strong
Genetics of suicide
B Bondy et al
337
genetically driven vulnerability.16 Although various
biological, psychological, sociological and economic
factors contribute to the complex aetiology of suicidal
behaviour, evidence for a genetic liability is convin-
cing since many years. Twin studies have shown that
monozygotic twins have a significantly higher con-
cordance rate for completed and attempted suicide
than dizygotic twins.17 This finding was replicated
in a large Australian twin study, in which the risk
of a serious suicide attempt by a monozygotic twin
was 17-fold increased if the co-twin made a serious
suicide attempt.18 Also adoption studies supported
the genetic component, as among the biological
relatives of an adoptee who committed suicide, the
rate of suicide is elevated about six times compared
to the biological relatives of non-suicidal adopted
persons (for review see Brent and Mann16). From
these data it was estimated that 43% of the variability
in suicidal behaviour may be explained by genetics,
while the remaining 57% may be explained by
environmental factors.17,19,20
The heritability of suicide and suicidal behaviour
seems to be determined through at least two compo-
nents: the heritable liability to psychiatric disorders,
and the heritable liability to impulsive aggression or
other personality traits. And thus the concordance of
both liability factors results in the highest risk for
suicidal behaviour.16
The neurochemistry of suicidal behaviour
Post-mortem brain analyses gave interesting data on
the serotonergic, noradrenergic and dopaminergic
neurotransmitter systems and the cellular morpho-
logy of suicide victims. Especially, the serotonergic
abnormalities, which are related to a variety of
psychopathological dimensions such as anxiety, de-
pressed mood, impulsivity and aggression, were the
focus of many investigations. The initial, seminal
finding by Asberg21 that a low cerebrospinal fluid
(CSF) 5-HIAA concentration could be related to the
incidence of violent suicidal acts, was repeatedly
replicated in higher lethality attempted suicides.21,22
A low brain serotonin (5-HT) turnover rate was
repeatedly found in impulsive violent offenders,
especially when being intoxicated.23
Post-mortem studies with brains of suicide victims
revealed evidence for reduced serotonin transporter
sites in the prefrontal cortex, hypothalamus, occipital
cortex and brainstem.24 In an autoradiographic study
this abnormality could be localized to the ventrome-
dial prefrontal cortex.25 Alterations were also obser-
ved on the receptor level, as postsynaptic 5-HT1A and
5-HT2A receptors were found to be upregulated in
prefrontal cortex and this increase was suggested as
being a compensatory mechanism to the low activity
of the serotonergic neurons (for review see Mann13). It
is interesting to note that the 5-HT1A upregulation
seems to be localized to the ventral prefrontal cortex,
a region that is involved in behavioural and cogni-
tive inhibition,25 and low serotonergic input might
Molecular Psychiatry
 Genetics of suicide
B Bondy et al
338
contribute to impaired inhibition, creating a greater
propensity to act on suicidal or aggressive feelings.13
These post-mortem findings are underlined by a
challenge investigation with fenfluramine, which
induces an increase in prolactin secretion in healthy
people, but in suicide attempters with a higher degree
of lethality, the increase is more blunted.26 As pro-
lactin secretion is an indicator of central serotonergic
function, the results of Malone et al. suggest some
dysfunction in the serotonergic system in suicide
attempters. Although some of the results are not
consistent and/or discussed as being related more to
major depression than to suicide,27 these results sug-
gest that the serotonergic activity is decreased in
suicidal behaviour.
Only few post-mortem studies covered alterations
of the noradrenergic or dopaminergic systems. The
main findings were decreased noradrenalin (NA)
levels in brainstem and increased alpha2-adrenergic
receptor densities, suggested as being upregulated
due to the NA deficit.28 The results with tyrosine
hydroxylase (TH), the rate-limiting enzyme for NA
and dopamine (DA) synthesis were divergent, as both
increased29 and decreased immunoreactivity were
observed.30 However, increased TH and alpha2-adre-
nergic receptor densities could be indicative of nor-
adrenergic depletion compensatory to increased NA
release. This hypothesis is important with regard to
the relation between the noradrenergic system and
stress response, as severe anxiety or agitation are
associated with noradrenergic overactivity, higher
suicide risk and overactivity of the hypothalamic-
pituitary-adrenal (HPA) axis.13
Results with the dopaminergic system are even
scarce. Overall, no alterations were found for mRNA
levels of the D1 and D2 receptor in the caudate nuclei
of suicide victims31 and similarly not for D4 receptor
binding.32 A recent in vivo investigation of homo-
vanillinic acid (HVA), the main DA metabolite, in
CSF of depressed suicide attempters demonstrated
reduced HVA levels in attempters, but not in
depressed non-attempters33 thus suggesting a relation
of DA to suicide but not to depression.
On the basis of the neurobiological findings, genetic
studies have been carried out since about a decade in
order to elucidate the genetic contribution to the
vulnerability of suicidal behaviour. As there is
convincing evidence that a serotonergic dysfunction
is involved in the biological susceptibility to suicide,
especially in high-lethality suicide, the majority of
the studies were performed with candidate genes of
the serotonin pathway. However, also newer aspects
deviant from the classical paradigms will be reviewed
here.
Tryptophan hydroxylase
Tryptophan hydroxylase (TPH) is the rate-limiting
enzyme in the biosynthesis of serotonin (5-HT),
converting the amino-acid tryptophan to 5-hydroxy-
tryptophan (5-HTP) which is further decarboxylated
Molecular Psychiatry
into 5-HT. Thus, TPH is a critical component for the
amount of 5-HT available in the synaptic cleft and the
TPH gene was among the first candidate genes for
association studies of suicidality. In the meantime,
two different TPH isoforms have been identified,
referred to as TPH1 and TPH2, the genes for both
being located on different chromosomes, chromosome
11 and 12, respectively.34 It is further known that
TPH2 is expressed in brain but not in peripheral
tissues in mice34 and in men,35 and the TPH2 is thus
considered as the brain-specific enzyme, whereas
TPH1 is responsible for peripheral serotonin genera-
tion.36 At present it is not completely clarified
whether TPH1 is also expressed solely in the
periphery in humans, as both TPH1 and TPH2 mRNA
could be identified in various human brain regions,
although TPH2 mRNA levels were about fourfold
higher than that of TPH1 in the raphe nuclei.37
The data concerning the enzyme TPH as a pre-
synaptic marker in post-mortem brains of suicide
victims were unequivocal for a long time. Ono et al.38
found no overall difference in TPH immunoreactivity
between suicide and control brains. Later on, Bonkale
et al.39 studied TPH immunoreactivity in specific
subnuclei of the dorsal raphe and again observed
no differences between depressed suicide victims
and controls. In contrast, a recent investigation by
Boldrini et al.40 found TPH immunoreactivity to be
higher in dorsal raphe nucleus of suicide victims and
proposed a compensatory mechanism to alleviate the
cortical serotonin deficit. Two recent studies investi-
gated the TPH2 mRNA either by in situ hybridization
or quantitative real-time PCR. Bach-Mizrachi et al.41
reported higher levels of TPH2 mRNA in drug-free
suicides throughout the entire extent of the rostro-
caudal axis of the dorsal raphe nucleus and explained
their findings as homeostatic response to deficient
brain serotonergic transmission. Investigating pre-
frontal cortex a greater amount of TPH2 mRNA was
found, this however did not differ significantly
between suicides and controls.42 In evaluating these
discrepant results one has to acknowledge that differ-
ent areas were investigated in the different studies
and that the studies that have been carried out before
the identification of TPH2 did not distinguish
between the two isoforms of the enzyme.
All together the discovery of TPH2 was supposed to
explain all the previously puzzling data in the past 30
years about divergent protein/mRNA ratios and
biochemical characteristics of TPH from peripheral
sources and from CNS.
The TPH1 gene
The TPH1 gene is located on chromosome 11p15.3–
p14 and has two common polymorphisms in intron 7
consisting of an A to C substitution at nucleotides 779
(A779C) and at 218 (A218C) which are in tight, but
not complete, linkage disequilibrium. Although the
AA genotype of the TPH1 A218C polymorphism was
associated with higher TPH immunoreactivity in 28
post-mortem brain samples than the other geno-

types,38 both variants are supposed not to alter the
amino-acid sequence or the TPH gene transcription.43
Further, four common variants have been identified
in the promoter region, as the T-7180G, C-7065T, A-
6526G, and G-5806T polymorphisms, and a signifi-
cant association was observed between the A-6526G
variant and suicidality in 167 Finnish offenders.44
Originally the A779C polymorphism was classified
as U and L (upper and lower band) and Nielsen et al.45
were the first who reported an association between
the UU genotype and higher CSF 5-HIAA concentra-
tion in a group of violent alcoholic offenders, whereas
the LL genotype had the lowest 5-HIAA levels.
Further, a significant association of the TPH1 A779C
polymorphism emerged with a history of violent
suicide attempts, as only two of the 36 suicide
attempters had the UU genotype in contrast to 10
out of 34 probands who never attempted suicide.45
This finding was replicated by the same group in an
extended study with 804 Finnish alcoholic offenders,
controls, and their relatives, altogether a sample that
included 369 sib pairs. Again the L-allele showed
significant evidence for linkage to suicidality in
affected sib pairs (P = 0.006), severe suicide attempts
in unaffected sib pairs (P = 0.01), alcoholism in
unaffected sib pairs (P = 0.002) and to the Karolinska
Scales of Personality socialization score (P = 0.002).46
The authors concluded that the A779C variant of the
TPH1 gene might predispose to suicidality but this
association was discussed as being relevant mainly
among impulsive offenders, as they are phenotypi-
cally more extreme.23,46 These studies were extended
by Roy et al.,47 who observed an excess of the TPH
779C allele (L-allele) in 24 surviving Swedish co-
twins of monozygotic twin suicide victims. However,
a contradictory result emerged from a subsequent
study, as the less common A779 allele (U-allele) was
more frequent in depressed suicide attempters.48
Many studies followed these first reports and most
of them investigated the A218C polymorphism. The
majority of studies were carried out in the frame of
association studies with depressed, bipolar, schizo-
phrenic or alcoholic patients. Although the numbers
of patients within the diagnostic categories seemed to
be sufficient, those with suicidal attempts were small
in most studies. Nevertheless, Mann et al.,48 found an
excess of the A218 allele in suicide attempters among
patients with depressive disorder in American Cau-
casians. Similarly, in a multicentre study investigat-
ing a large cohort of patients from several European
countries, Souery et al.49 observed the CC genotype of
the A218C polymorphisms less frequently in unipolar
patients with a history of suicide attempts, but not in
bipolar patients. Investigating seven polymorphisms
spanning the entire gene in 231 individuals who
attempted suicide, significant associations were
found between violent suicide attempt and variants
in introns 7, 8 and 9 (which are in complete linkage
disequilibrium) and in the 3-non-coding region that
encodes for the catalytic part of the enzyme.50 Turecki
et al.51 focused on polymorphisms in the promoter
Genetics of suicide
B Bondy et al
339
region (A-6526G and G-5806T) which were investi-
gated together with the intron 7 A218C variant in 101
suicide completers from the French-Canadian popu-
lation. In contrast to the fact that the single loci were
not associated with suicide, a haplotype analysis
revealed that one haplotype (
6526G
59061T 218C)
was significantly more frequent among violent sui-
cide victims than in normal controls (w2 = 11.3, df = 2,
P = 0.0008; OR = 2, CI:1.3–3.6).
Concerning the relation between personality traits
and the TPH1 gene it is noteworthy that two
independent studies observed a relation between the
A779 allele and aggressive disposition in healthy
individuals without psychopathology. In both stu-
dies, investigating probands of American52 and Ger-
man descent53 the U-allele scored significantly higher
on measures of aggression, irritability and anger-
related traits.
However, the positive results could not be repli-
cated in all studies and the list of negative findings
is long. Post-mortem analyses with DNA derived
from suicide victims yielded negative results for 47
depressed Caucasians suicide victims,54 35 depressed
suicide victims of Canadian origin55 and for 160
deceased males of Slavic origin.56 Two groups investi-
gated the TPH1 polymorphism in Japanese suicide
victims, but both failed to demonstrate an association
between suicide and the A-6526G and A218C poly-
morphism.57,58 Also studies with Caucasians suicide
attempters of different diagnostic categories yielded
negative results between suicide attempts in unipolar
and bipolar patients54,59,60 or alcohol-dependent
patients,61 although some of the studies identified
an association between the A218C polymorphism and
the disorder in question. A case–control family-based
study in Ashkenazi and non-Ashkenazi Jewish ado-
lescents again revealed no significant allelic associa-
tion with the A218C polymorphism.62 Interestingly
and in contradiction to the findings with suicide
victims of the Japanese population, 218C homozy-
gotes were overrepresented in Korean schizophrenic
patients with suicidal behaviour.63 Tsai et al.64 have
observed an association between the 218C homozy-
gotes and suicidal attempts in Chinese patients with
major depression but not with bipolar disorder.
However, Kunugi et al.65 could not relate both the
A218C and A779C polymorphisms to a history of
suicidality among Japanese unipolar or bipolar
patients, thus being in agreement with the findings
in completed suicide.
Owing to the discrepancy of the results together
with the small numbers of patients, the diagnostic
heterogeneity with either committed suicide as clear-
cut act or a history of suicidal attempts, and finally
due to the use of the different markers the impact of
the TPH1 gene on suicidal behaviour remains still
ambiguous. Almost all studies lacked in statistical
power, ethnic heterogeneity and variations in the
sampling strategy, in particular for controls. Three
meta-analyses were carried out in the recent years to
pool results from individual studies and in order to
Molecular Psychiatry
 Genetics of suicide
B Bondy et al
340
test, whether the TPH1 gene intron 7 polymorphisms
affect the vulnerability for suicidal behaviour. Lalovic
and Turecki66 have selected 17 studies for the analysis
and carried out two meta-analyses. One compared
suicide attempters or completers (n = 1290) with 2295
healthy controls; the other compared suicide attemp-
ters (n = 625) with non-attempters (n = 1475), but
none of these analyses provided evidence for asso-
ciation (OR = 1.14, 95%CI 0.97–1.34 for the first; and
OR = 0.96, 5%CI 0.77–1.2 for the second study). Also
the combined results from both analyses showed no
overall association between suicidal behaviour and
the intron 7 A218C polymorphism of the TPH gene.
A subsequent meta-analysis by Rujescu et al.67
observed no significant differences in genotype or
allele frequencies for 147 suicide attempters with
violent or non-violent means, but a weak yet highly
significant association was observed in a meta-
analysis including these data together with those of
seven studies investigating the A218C polymorphism
(OR = 1.33; 95%CI 1.17–1.5, P = 0.00002) in Caucasian
suicide attempters. This association could be repli-
cated by a further, more refined meta-analysis by
Bellivier et al.68 The authors assessed the hetero-
geneity due to variations in genetic background toge-
ther with the polymorphisms studied and nine
studies fulfilled the inclusion criteria. Thus by im-
proving the quality of the sample, the authors found
a significant association between the A218C poly-
morphism and suicidal behaviour using the fixed
effect method (OR = 1.62; 95% CI 1.26–2.07) and the
random effect method (OR = 1.61; 95% CI 1.11–2.35).
Even after removing two studies, which deviated from
the calculated global effect (one positive and one
negative), the meta-analysis revealed a significant
association and suggested that the A-allele has a dose-
dependent effect on the risk of suicidal behaviour,
at least in the Caucasian population.
The THP2 gene
The identification of the brain-specific, second iso-
form TPH2 gene,36 being located on chromosome
12q15, promised a step forward in investigating the
genetic contribution to suicidality, as this isoform
apparently plays a more important role in the
synthesis of brain serotonin and thus might be a
better candidate gene. However, so far the number of
studies using TPH2 as candidate gene is rare. Zill
et al.69 from our group carried out a SNP, haplotype
and linkage disequilibrium study with 263 German
suicide victims with 10 SNPs defining a 28-kbp gene
region in the TPH2 gene, across which linkage
disequilibrium is high. We observed significant asso-
ciation between one SNP and suicide (P = 0.001,
global P = 0.01). Additional haplotype analyses pro-
duced support for association (P < 0.0001, global P =
0.0001). Although a subsequent study could not
demonstrate the influence of a polymorphism in the
promoter region (T–473A) and a marker in intron 1
(hCV245410)70 on suicidal behaviour in schizophre-
nic patients,71 there was a recent supportive evidence
Molecular Psychiatry
for TPH2 haplotype linkage to anxiety/depression
phenotypes and suicide attempts in two popula-
tions.72 Zhou et al.72 investigated different markers
in the 50 -promoter and 30 -untranslated region and a
15-locus panel spanning 106 kbp of the TPH2 gene in
1798 cases and controls of four ethnic groups for
association with suicide attempt, anxiety, major
depression and CSF 5-HIAA as neurochemical inter-
mediate phenotype. They identified a haplotype
block of 52 kbp in size, which increased in frequency
in suicide attempters in Finnish whites and African
Americans and which was further associated with the
CSF 5-HIAA concentration. Moreover, this haplotype
resembles that investigated by Zill et al.69 Although
the functional consequences of these polymorphisms
are unknown and although the data on the TPH2 gene
are really limited, the TPH2 gene deserves further
evaluation as candidate gene for suicidal behaviour.
The serotonin transporter
The serotonin transporter (5-HTT) is terminating the
5-HT action via uptake of this neurotransmitter from
the synaptic cleft and thus the density of 5-HTT sites
is regarded as an important index of 5-HT function.
The human 5-HTT gene, being located on chromo-
some 17, has a common polymorphism (5-HTTLPR)
in the 50 -regulatory region due to a 44-bp deletion
which results in either the S- (short) or L- (long)
allele.73,74 The presence of the S-allele was associated
with reduced transcriptional activity and lower level
of gene expression, lower levels of 5-HT uptake in
transformed lymphoblastoma cell lines and with
anxiety-related traits.74 In a comprehensive study,
Mann and co-workers investigated a possible relation
between the 5-HTTLPR and 5-HTT binding in
prefrontal cortex, assayed by quantitative autoradio-
graphy in 159 post-mortem brain samples. Although
they could replicate the finding of reduced 5-HTT
binding in prefrontal cortex in major depression and
suicide, they observed no relation between 5-HTTLPR
genotypes and 5-HTT binding.75 A study of our group
with 72 controls and 72 alcoholics has shown that
also in periphery, using platelets as peripheral model
for the central serotonergic system, no relation
between 5-HTT binding (3[H]-paroxetine sites) and
the 5-HTTLPR genotypes were found, neither in
healthy controls nor in alcoholic patients.76
Despite these still open questions about the func-
tion of the insertion/deletion polymorphism it was
hypothesized that the short form of the 5-HTT gene
might be associated with impulsive aggression and
suicidal behaviour. We have carried out a study using
genomic DNA from 58 Caucasian suicide victims and
found an association of the S-allele and completed,
mainly violent, suicide (OR = 2.08; 95%CI 1.3–3.2;
P = 0.001).77 This finding could be replicated in a
subsequent study with 51 Caucasian depressed,
violent suicide attempters,78 but not with suicide
victims from an isolated Canadian79 or American
population.75

In agreement with our results, an association was
found between the S-allele and violent suicide
attempts of Caucasian bipolar80 and schizophrenic
patients,81 although in the latter study there was no
correlation between the genotypes and impulsivity,
assessed with the BIS (Barratt’s Impulsivity Scale).
Moreover, the association between the S-allele and
suicidal behaviour seems to be independent of
clinical diagnosis, demographic or socio-cultural
parameters. Campi-Azevedo et al.82 carried out a
study in depressed and schizophrenic patients of
the Brazilian population, which is very heteroge-
neous, and they found that the S-allele carriers are
overrepresented among persons who committed sui-
cide and moreover these patients attempted suicide
more frequently and had higher lethality scores.
The relation between the S-allele and violent
suicide methods was underlined in a study by Courtet
et al.83 who clearly demonstrated that the frequency
of the SS and SL genotypes was not increased in
patients with non-violent suicide attempts. The same
authors have published a follow-up study with 103
patients and found that patients who reattempted
suicide during a 1-year follow-up period had a
significantly higher frequency of the S-allele and
the SS genotype.84 As it is known that patients are at
high risk for reattempt and for completed suicide
within the first year following a suicide attempt,
these authors proposed that the presence of at least
one S-allele might be an important predictor for
subsequent suicide attempts.
The relation of the S-allele of the 5-HTTLPR and
some personality traits was not only shown in
suicidal behaviour but also in alcohol- or heroin-
dependent persons. Sander et al.85 found that anti-
social alcoholics carrying the SS genotype exhibited
significantly lower scores on harm avoidance and
higher novelty-seeking scores. Similarly, the SS
genotype was more frequent among a group of violent
heroin-dependent persons compared with addicted
individuals without aggressive behaviour86 and was
further associated with an increased availability to
experiment illegal drugs, particularly in subjects with
more aggressiveness.87
Gender-specific associations of the 5-HTTLPR and
suicide were proposed in a study enrolling 180
Spanish suicide attempters (121 women and 59
men) by Baca-Garcia et al. The S-individuals (SS or
SL) were significantly overrepresented among female
attempters and especially in those who had unsuc-
cessfully tried to commit suicide.88 In contrast, in a
sample of 100 French Caucasian alcohol-dependent
patients (48 men, 52 women), the presence of the
S-allele was related to a lifetime risk of suicide
attempts, but only in male subjects.89 Previous
association studies also observed a overrepresentation
of the S-allele in suicide attempters in a sample of
French90 or German alcoholic patients;91 however,
females were underrepresented in both studies and
thus the results were not analysed as a function of
gender. An explanation for this discrepant data and
Genetics of suicide
B Bondy et al
341
the gender-specific effect might be that intermediate
links between alcohol dependence and suicidal
behaviour may involve different genetic factors in
men and women. A recent study investigating the 5-
HTTLPR in the continuum between compulsivity and
impulsivity in females observed that the frequency of
S-individuals (either homo- or heterozygotic) was low
in patients with OCD, intermediate in non-impulsive
controls and higher (82%) in impulsive suicide
attempters92 and thus it was suggested that genetic
variants may be related more likely to behavioural
dimensions instead of to specific psychiatric dis-
orders.
In contrast to these positive findings a variety
of studies did not observe an association of the
5-HTTLPR with suicidality, neither in post-mortem
studies75 nor in studies investigating DNA of suicide
attempters from Caucasian,93,94 Chinese95,96 or Jewish
Ashkeanzi origin.97 Even an increased frequency of
the low-activity L-allele was observed within a
patient group with increased hopelessness and
suicide ideation.98 Du et al.99 found in a very small
sample of 24 probands that the L-allele was more
frequent in suicide victims, and these authors obser-
ved more instead of less 5-HTT binding sites in
platelets of S-allele carriers.
Also the relation between familial suicidal beha-
viour and the history of suicide attempts have been
investigated and has yielded discrepant results. One
study found an association between suicidal family
history and suicide attempts in 237 probands with
major depression or schizophrenia as well as first-
and second-degree relatives, but no association to the
5-HTTLPR genotype.100 Another study found a rela-
tionship between family history of suicidality and
the SS genotype.101
Despite the many discrepant results there is still an
ongoing interest on genetic variants of 5-HTT as
possible indicator for suicidality. Two meta-analyses
were carried out in order to unravel the importance of
the 5-HTTLPR in suicidal behaviour. The analysis of
Anguelova et al.102 reviewed 12 studies with 1599
subjects and found evidence for a significant associa-
tion of the S-allele with suicidal behaviour. This
result was robust and remained significant following
sensitivity analysis. A more recent meta-analysis by
Lin and Tsai analysed the cumulative data from
primary literature in order to determine conclusively
the hypothesized role of the 5-HTTLPR. The authors
have performed three meta-analyses comparing the 5-
HTTLPR between suicidal subjects and controls,
between suicide attempters and non-attempters of
the same psychiatric diagnoses and finally between
violent or non-violent suicidal subjects compared
to normal controls. The authors found no association
between the 5-HTTLPR and suicidal behaviour.
However, comparing the suicide attempters with
non-attempters within one diagnostic category, per-
sons with at least one S-allele were more frequent
among suicide attempters (P = 0.004). A further find-
ing was that the S-allele was associated with violent
Molecular Psychiatry
 Genetics of suicide
B Bondy et al
342
suicide (P = 0.001), but not with non-violent sui-
cide.103 In summarizing all the studies with inade-
quate number of patients and controls, this study
provides significant evidence supporting the role of
the 5-HTTLPR S-allele with suicidal behaviour,
especially with violent suicide.
Based on the identification of variable-number-
tandem-repeats in intron 2 (VNTR-2) of the 5-HTT
gene some studies were carried out with this variant
to identify a possible liability to suicidality. No
association was observed to bipolar disorder or suici-
dality in a Canadian family study104 and in Canadian
suicide attempters.105 Similar negative findings were
derived for Chinese mood disorder patients with
suicidal history106 or psychotic patients with suicidal
behaviour.95 Using DNA of Croatian suicide victims
there was also no association between suicide and the
VNTR-2 variants. However, a combined analysis of
the 5-HTTLPR and VNTR-2 provided evidence to-
wards an increase of 5-HTTLPR L-allele and VNTR-2
allele 10 in the suicide victim group, which was
however of low significance.107
Serotonin receptors
The 5-HT2A receptor
There is considerable evidence that the density of the
5-HT2A receptor is upregulated in parietal cortical
regions of depressed suicide victims (for review see
Mann13) and it was suggested that this increase may
be at least partly be regulated genetically.108 The
importance of 5-HT2A receptor upregulation as
marker for suicidality was further underlined by a
recent investigation showing that in suicide brains
the lifetime aggression scores correlated positively
with 3H-ketanserin binding in all investigated pre-
frontal Brodman areas.109 Further, several studies
with platelets of suicide attempters showed an
upregulation of 5-HT2A receptor as a peripheral
marker for suicidality,110,111 although a critical review
claimed that methodological flaws limited the valid-
ity of platelets as biological model.112
The 5-HT2A receptor gene is located on chromo-
some 13q14–q21 and according to the current SNP
databases more than 200 single-nucleotide poly-
morphisms (SNPs) are identified spanning the
gene;113 only a small number of them have been
investigated as candidates in psychiatric disorders,
most notably the T102C and A-1438G variants.
However, the genetic findings of associations between
5-HT2A receptor gene variants and suicide have been
controversial. Du et al.114 reported an association of
the 5-HT2A receptor 102C-allele with suicidal idea-
tion in 78 Canadian patients with major depression
(w2 = 8,5; df = 1; P = 0.005). They found that patients
with the CC genotype had significantly higher scores
in HAMD item 3 score (indication of suicidal
behaviour) than TC or TT genotypes and concluded
that the 5-HT2A receptor 102C allele might confer
increased risk for suicidality independently of psy-
chiatric diagnosis. In this context it is remarkable that
Molecular Psychiatry
in an earlier study, genotyping DNA from 24 suicide
victims, these authors found no association between
the 5-HT2A receptor 102C allele and suicidality.99
A similar positive finding was obtained in a sample
of Spanish depressed patients, where significant
differences in both allele and genotype distribution
were observed between 126 non-suicide and 33
suicide attempters.115 Moreover, 5-HT2A 102C allele
carriers had more than five times the risk for
attempting suicide than non-carriers (OR = 5.5; 95%
CI 1.18–35.2).
In the light of the findings of Du et al.,114 several
studies have been carried out among different
diagnostic groups and different ethnicities. However,
no associations were found with suicidal behaviour
in the Caucasian population comprising alcoho-
lics with suicidal ideation and previous suicide
attempts,116 schizophrenics with suicidal ideation117
or suicide attempts.118,119 Results were also negative
in the Jewish97 or Brazilian120 population. Similarly,
investigating the closely linked A-1438G polymor-
phism, no convincing association was found in
the Caucasian121 and Japanese patients with suic-
idality.122
As completed suicides are more homogeneous in
terms of higher lethality and are thought to be more
influenced by serotonergic mechanisms than attemp-
ted suicides,7 we and others examined whether one of
the 5-HT2A receptor polymorphisms was associated
with completed suicides, irrespective of the under-
lying clinical diagnosis. Neither the A-1438G nor the
T102C polymorphism were associated with com-
pleted suicide in 151 Japanese,123 131 Caucasian124
or 68 Australian suicide victims.125 However, one has
to take into account that in none of these studies
a psychological autopsy was available, and therefore
no information about the proportion of depressed
patients in these samples.
A recent systematic review and meta-analysis of
suicide association studies, enrolling suicide attempt
or completion but not ideation, found no associa-
tion with the 5-HT2A T102C variants.102 One of the
explanations for the conflicting finding might be the
size of the sample in both positive studies and/or
ethnic stratification. Considering all data published
since 1996, it becomes obvious that small but albeit
important ethnic differences between Caucasian and
non-Caucasian probands exist; as in Chinese and
Japanese population, the frequency of the T-allele is
slightly higher than in the European sample.124 Thus,
one reason for the discrepant result might be the fact
that the sample of Du et al. consisted of French
Canadians who might have a different ethnic back-
ground than the other samples. However, overall
there is little proof that the 5-HT2A receptor gene
is involved in liability to suicidality.
Other serotonergic receptors
Negative feedback inhibition of raphe neurons is
mediated by somatodentritic 5-HT1A autoreceptors
and it is known that several antidepressants desensi-

tize raphe 5-HT1A autoreceptors thereby resulting in
enhanced serotonergic transmission.126 Conversely,
post-mortem brains from depressed suicide victims
displayed increased 5-HT1A receptor density in the
raphe nuclei but not at postsynaptic sites, which is a
further hint towards a decreased serotonergic acti-
vity.127 Although it is not established as to whether
this upregulation is associated with depression or
with suicide, the 5-HT1A receptor gene became a
candidate for vulnerability studies in suicide.
Huang et al. have genotyped almost 700 psychiatric
subjects for a common polymorphism (C–1019G)
within the promoter region of the 5-HT1A receptor
gene. Data were related to psychopathology and
diagnoses, and associations in genotypes and allele
frequencies were observed for substance abuse dis-
order, schizophrenia and panic attacks, but not for
suicidal behaviour.128 Recently, this polymorphism
was investigated in suicide completers and patients
with major depression in separate cohorts (all
Canadian Caucasian), and in both groups the homo-
zygous
1019G allele was found to be enriched, in
the suicide groups even fourfold as compared to
controls.129 According to the hypothesis and model of
these authors, this polymorphism prevents binding of
the transcriptional repressor NUDR, thereby resulting
in enhanced 5-HT1A receptor expression and affect-
ing the serotonergic system in limbic and cortical
areas.129–131 Two further structural polymorphisms in
the 5-HT1A receptor gene which lead to an exchange
of amino acids, the Pro161Leu and Gly272Asp
variants, were not associated with suicide in Japanese
suicide victims.132
Using a mice knockout model being deficient for
the 5-HT1B receptor it was suggested that aggressive
behaviour might be mediated via this receptor thus
making the 5-HT1B receptor gene a candidate for
evaluating the liability to suicidality. Two common
polymorphisms were identified in the human gene
(chromosome 6q13–15), a silent C to T substitution at
nucleotide 129 and a silent G to C substitution at
nucleotide 861; it was shown that the G861C poly-
morphism and a closely linked short tandem repeat
locus D6S284 are involved in the control of aggression
and impulsivity, as in Finnish, as well as South-
western American Indians antisocial alcoholics had a
significantly higher 861C allele frequency.133 This
finding is supported by a study with German alco-
holics, where a lower frequency of the 861C allele was
observed in alcohol-dependent patients with anti-
social personality traits and conduct disorder.134
However, no association was found with suicide,
depression, alcoholism or pathological aggression in a
large sample of 696 unrelated American psychiatric
subjects135 and in German suicide attempters.136
Similarly negative were the results in a study
combining 245 German and 118 Slavic suicide
victims137 and in suicide victims of Japanese origin.138
Further polymorphisms in the coding and in the
promoter region were identified, as the common A–
161T polymorphism in the promoter region139 but two
Genetics of suicide
B Bondy et al
343
subsequent studies did not find an association to
attempted suicide and aggression in Chinese schizo-
phrenics140 or in Chinese depressives.141
The other serotonin receptors gained so far less
attention and investigations with the 5-HT2C recep-
tor,142 the 5-HT6 receptor143 or a combined investiga-
tion of seven serotonergic receptor genes revealed no
hints of being involved in suicidality.144
This constantly negative finding on the serotonin
receptors other than the two positive findings with
the 5-HT2A receptor gene, demonstrates that they
seem not to have an impact on the liability for
suicidality. Despite these discrepant results, it cannot
be ruled out that a locus predisposing to antisocial
alcoholism may be linked to the 5-HT1B receptor,
thus making it worthwhile to be investigated further
as a candidate for suicidal behaviour as elevated
impulsive aggression is one of the most prominent
characteristics of violent suicide.
Genes involved in transmitter synthesis
and degradation
Tyrosine hydroxylase
Central monoamines are important modulators of
mood and behaviour and a deficit in both serotonin
and NA play an important role in the pathophysiol-
ogy of stress and the response to stress reactions.145
Thus, tyrosine hydroxylase (TH), the rate-limiting
enzyme in the synthesis of adrenaline, NA and DA
might be an interesting candidate for genetic suicide
research. Nevertheless, there was so far not much
interest in this gene, as only one study investigated
the tetranucleotide repeat polymorphism within the
first intron of this gene.146 Persson et al. genotyped
Swedish suicide attempters of different diagnostic
categories but found no overall differences in the
allele frequencies when all suicide attempters were
compared to controls. However, they observed a
significant higher incidence of the TH-K3 allele
(252 bp) among attempted suicide in patients with
adjustment disorders147 and it was proposed that this
allele might reflect predisposition for a common
phenotype with altered vulnerability for psychiatric
disorders.
Monoamine oxidase A
Monoamine oxidase A (MAOA) is a mitochondrial
membrane enzyme that is involved in human beha-
viour due to its key role in the metabolism of
biological amines.148 The general idea underlying
the investigation of MAOA activity in relation to
violent behaviour is that low MAO activity results in
elevated levels of serotonin, NA, and DA in the brain,
manifesting as mood disorder and/or aggressive beha-
viour.13 Several finding with peripheral tissues under-
lined its importance, as low platelet MAO activity has
been connected with personality traits like impul-
siveness, sensation seeking, monotony avoidance and
increased psychiatric morbidity149 which all seem to
Molecular Psychiatry
 Genetics of suicide
B Bondy et al
344
predispose for violent behaviour and increased risk
for antisocial and criminal acts.150
Interest in the MAOA gene as a putative candidate
for suicide research is derived from the first exciting
study by Brunner et al. who showed that a point
mutation in the MAOA gene observed in a Dutch
kindred was associated with violent behaviour and a
phenotype bearing some resemblance to the manic
syndrome.151 Although this mutation is rare, the
report emphasized that a variant within the MAOA
gene might be a liability factor for aggressive
behaviour and finally for suicidality.
A number of polymorphisms have been described
for the MAOA gene. A 30-bp repeated sequence being
located 1.2 kbp upstream of the MAOA coding
sequences and being present in 3, 3.5, 4 or 5 copies
has been shown to affect the transcriptional activity of
the gene. Alleles with 3.5 or 4 copies of this 30-bp
tandem repeat (uVNTR) are transcribed 2–10 times
more efficiently than those with three or five copies of
the repeat.152 Further, two restriction fragment length
polymorphisms (EcoRV and Fnu4HI) were identified
with a 30-fold difference in enzyme activity.153
This 30-bp VNTR has attracted much interest in
psychiatric studies. Manuk et al.154 reported that
healthy men carrying the high activity alleles (3.5 and
4 copies) expressed a lower CNS serotonergic respon-
siveness in the fenfluramine challenge test and more
impulsive aggression. Although a subsequent study
could not replicate the impact of this functional
polymorphism on the expression of personality
traits,155 an influence of this polymorphism on the
serotonin metabolism with altered CSF 5-HIAA
concentrations could be shown in female156 and
male157 volunteers. Further, some studies showed
associations with bipolar disorder and major depres-
sion but also to aggression and impulsivity in
antisocial alcoholism (for review see Hattori et al.158).
Concerning suicide the results are not convincing
as no association was identified for the MAOA
uVNTR variant and only a weak association
(P = 0.016) of the Fnu4HI locus with a history of
suicide attempts in female bipolar patients, but not in
males.159 Further studies failed to find an association
between suicidality and the MAO uVNTR in heroin-
dependent subjects of Italian descent,160 in Japanese
unipolar and bipolar patients159,161,162 or Japanese
suicide victims.162 Only in the study by Du et al.163
a positive result with the MAOA gene was observed.
This Canadian group investigated a restriction frag-
ment length polymorphism at position 1460 (EcoRV)
in post-mortem brain samples from 44 depressed
suicide victims and differences in genotype/allelic
distributions were found for the male group (n = 33),
but not for females.
A recent study by Courtet et al.164 investigated the
uVNTR and a dinucleotide repeat in intron 2, which
both are in linkage disequilibrium in 738 West
European Caucasians with previous suicide attempts.
In agreement with the previous studies, there was no
overall association between the MAOA variants and
Molecular Psychiatry
suicidality; however, the frequency of the high
activity alleles was higher in men who had attempted
violent suicide than in men who had used non-
violent means (OR 2.17, 95%CI 1.08–4.35). Although
at present there seems to be no relation between the
MAOA gene and the vulnerability for suicidality,
especially the finding by Courtet et al.164 strengthens
the hypothesis that an excess of high-activity MAOA
gene promoter alleles may influence the methods
used in suicide attempts.
Catechol-O-methyltransferase (COMT)
As there is some evidence that NA and DA are
contributing to aggressive behaviour and suicidal-
ity,165 COMT, the major catecholamine-degrading
enzyme is of potential interest as candidate genes
for suicidal behaviour. The COMT gene has a
functional common genetic polymorphism that is
responsible for substantial variability in COMT enzy-
matic activity. At position 158, a valine (Val) is
replaced by methionine (Met) and the Val allele is
associated with a relatively high activity (H-allele),
whereas the Met allele is associated with relatively
low activity (L-allele).166 Although there is presently
no evidence about an association between this
polymorphism and core diagnoses in psychiatry, it
was shown that the clinical phenotype within
different diagnostic categories might be influenced
by this variant. Thus, across different ethnic groups it
was shown that schizophrenic patients with the Met
allele had a higher propensity for violence.167–169
Although early studies were unable to identify an
association between the low-activity allele and suici-
dal behaviour or violence,98,170 some studies have
shown the low-activity allele being more frequent in
Finnish and Amercian Caucasian suicide attemp-
ters171 and in male Japanese suicide completers.172 A
recent study investigating families with at least one
member having bipolar disorder and suicidal ideas or
attempts, observed no association to the COMT
variants, but one has to take into account that females
comprised > 60% of the sample and that the associa-
tion might be more pronounced in males.173
The dopaminergic and noradrenergic system
The interest in the DA system, including DA receptors
and the DA transporter, derives from the involvement
of this system in several psychiatric disorders,
especially in alcoholism and its relationship to the
reward syndrome which is mediated via the DA D2
receptors.174 A deficiency or absence of DA D2 recep-
tors then predispose individuals to a higher risk for
multiple addictive, impulsive or compulsive beha-
viours175 and a polymorphism in the D2 receptor gene
(TaqI) was repeatedly investigated as risk for addic-
tive behaviour, however, with inconsistent results
(for review see Noble176). A recent study investigated
an insertion/deletion polymorphism within the pro-
moter region of the DA D2 receptor at position
141
(
141C Ins/Del), where one of two cytosines is

deleted upstream of exon 1 in the 50 -regulatory region,
and this deletion shows a lower transcription acti-
vity.177 In a large sample of more than 1000 chronic
alcoholic patients of German descent, Putzhammer
et al.178 found that the D2
141C Ins/Del was related
according to a phenotype–genotype strategy, for
example, patients suffering from severe withdrawal
symptoms, seizure or delirium, family history posi-
tive alcoholics, and alcoholics with an antisocial
personality disorder. They observed
141C Del allele
to be significantly in excess in alcoholics with
positive family history and in alcoholics with suicid-
ality, although there was no association to the entire
group of alcoholics. From these results it might be
concluded that the DA D2 receptor might confer a risk
to suicidality in patients with high familial loading
for alcoholism.
Further, there was an extended discussion about an
association between the risk-taking behaviour and the
length of the DA D4 receptor (DRD4) gene exon III
repeat alleles (for review see Kluger179). However,
most studies revealed negative results, either with
Israeli suicidal patients,180 or with Swedish suicide
attempters.181
Sequeira et al.182 followed the concept of catecho-
laminergic participation in the etiology of suicidality
and studied genetic variations at four loci of the
alpha-2-adrenergic receptor gene in Canadian suicide
victims, three in the promoter region and one
functional variant (N251K) which leads to an amino-
acid exchange, and found that the 251K allele was
only present in suicide victims, although only in
three suicide cases.
Search for new candidate genes and miscellaneous
results
Despite the studies that followed the original con-
cepts and hypotheses of serotonergic dysfunction,
several recent studies expanded the research to
identify new mechanisms and candidate genes. Thus,
under the assumption that anxiety and stress res-
ponse are involved in suicidal behaviour,13 several
mechanism modulating these effects are gaining
importance. Especially the effects of cannabinoids
on anxiety-related responses, which involve endo-
cannabinoid receptors (CB1) and further corticotro-
pin-releasing hormone (CRH), g-aminobutyric acid
(GABA) as main inhibitory transmitter, and the neuro-
peptide cholecystokinin (CCK)183 were in the focus of
recent investigations. The importance of the endogen
cannabinoid system may be underlined by recent data
showing an upregulation of CB1 receptors together
with a concomitant increase of the receptor-mediated
[35S]GTPgammaS binding in prefrontal cortex of de-
pressed suicide victims.184 However, so far no studies
are available investigating CB1 receptor polymor-
phisms in relation to suicidal behaviour.
Concerning the association between GABA and
suicidality, Baca-Garcia et al.,185 who investigated a
dinucleotide repeat (CA)n polymorphism of the a3
Genetics of suicide
B Bondy et al
345
subunit of the GABA receptor (GABRA3) gene in 184
Spanish suicide attempters yielded a negative result.
A further study observed an association between
Japanese suicide victims and a common polymor-
phism in the cholecystokinin (CCK) gene promoter
(G-196A) in males, but not in females.186
Neurotrophins might play a role in the etiology of
mood disorders and suicidal behaviour, as a signifi-
cant reduction of BDNF mRNA levels was shown in
prefrontal cortex and hippocampus of suicide sub-
jects.187 The common Val66Met polymorphism of the
BDNF gene was investigated in Chinese unipolar and
bipolar patients, but no relation between the disorder
or a history of suicide attempts were observed.188 A
further study comprised a missense polymorphism
(S205L) of the low-affinity neurotrophin receptor
gene (p75NTR) which found a positive result in
Japanese suicide attempters.189 The possible involve-
ment of 14-3-3 epsilon, which is related to neurogen-
esis, was identified as possible candidate gene, as it
was upregulated using DNA microarrays with brains
of suicide victims.190 These authors investigated
several SNPs within this gene and found a haplotype
associated with completed suicide thus suggesting
that a dysregulation of neurogenesis might be invol-
ved in suicide.190
This latter study clearly eliminated the possibility
that microarray analysis provides the opportunity to
study thousands of genes at once and may thus give
a ‘snapshot’ about the brain gene activity before
completing suicide.191 Thus, microarray analysis is
especially useful to identify new candidate genes and
to gain new insight into the biological mechanism of
suicide beyond the serotonergic system. Despite the
fact that there are several methodological pitfalls, as
post-mortem delay and the quality of the mRNA
preparation, microarray analysis has become a stan-
dard tool in many areas of biomedical research.192
Conclusions
As there is abundant evidence that the serotonergic
transmission plays a pivotal role in individual
differences in mood, impulsiveness and aggression,
and that intent to die and lethality are correlated
positively with abnormalities in the serotonergic
system, it is no surprise that molecular genetic studies
in suicide research focus on serotonergic genes. In the
last decade, a growing number of molecular genetic
studies have been carried out to identify candidate
genes that may be involved in the pathophysiological
mechanisms of suicidal behaviour. Despite tremen-
dous effort and a plenty of investigations, only two
genes, one coding for the tryptophan hydroxylase 1
(TPH1 A218C) and the other for the serotonin
transporter (5-HTTLPR), were reliably suggestive to
be involved in the vulnerability for suicidal beha-
viour.
In summarizing all findings with TPH1 it seems as
to whether the intronic polymorphisms A779C and/or
A218C are associated with suicidality via serotonergic
Molecular Psychiatry
 Genetics of suicide
B Bondy et al
346
dysfunction, (reflected by the low 5-HIAA), Courtet
et al.10 suggested that TPH may be a quantitative
risk factor, where a greater effect of the gene leads to
more pronounced serotonergic dysfunction with
higher levels of anger and more severe suicidal acts.
Concerning the brain-specific TPH2 gene, the results
published until now are promising attempts but far
from being conclusive.
The S-allele of the serotonin transporter poly-
morphism (5-HTTLPR), which plays a role in mood
disorders193 and in the response to antidepressive
medication,194 was further shown to be involved in
violent behaviour in subjects with type II alcohol-
ism85 and aggressive behaviour in heroin addicts.86
These data, together with the results of the association
studies in suicidal behaviour, favour the assumption
that the serotonin transporter gene is not involved in
suicidal behaviour in general, but in violent and
repeated suicide attempts. In contrast to this, the data
with the MAOA gene, which was repeatedly and
consistently associated with impulsive-aggressive
personality traits, do not propose a direct relation to
suicidal behaviour, but it might orient an act towards
violence in subjects with other suicide risk factors.10
Predominantly negative were the findings with any
type of the serotonin receptors and not convincing for
studies with catecholamine-synthesizing and -meta-
bolising enzymes or with the dopaminergic receptors.
One has to concede that the majority of the studies
were case–control association studies, which are
hampered by many pitfalls.195 A major concern is
that the sample size was often very small (below 50
cases) and thus could not provide enough statistical
power to detect an effect of minor genes and ethnic
stratification between cases and controls would hide
spurious associations between a genetic marker and a
disorder.
Further, the phenotypes investigated were different
from study to study, as persons with suicidal ideation,
suicide attempts and completed suicide were inves-
tigated. Especially for suicide ideation there is an
ongoing discussion as to whether there is a similar
genetic component as that demonstrated for suicide
attempts and completed suicide. It was even pro-
posed to exclude suicide ideation from the ‘biologi-
cal’ spectrum of suicidal behaviour196 as the familial
transmission of the risk of suicide was not linked to
suicidal ideation.197 On the other hand, a study by
Statham et al.18 proposed that genetic factors could
also affect suicidal ideation, and he estimated that
the heritability is 43% for suicidal thoughts. As a
consequence of these discrepant findings it was
suggested that the existence of a genetic component
in suicidal ideation should be tested in separate
studies, as even the neurobiological mechanisms
might be different from those in suicide acts.10
Suicidal behaviour is a complex disorder and thus
the predisposition towards suicide consists of numer-
ous genetic factors, which manifest themselves as
suicidal behaviour only when a certain threshold of
predisposition is crossed.198 Further, genes interact
Molecular Psychiatry
not only among each other but also with environ-
mental factors, but so far only little attention has been
paid to this possible interplay. A positive example in
this direction is the study by Caspi et al. who tested
why stressful experiences lead to depression in some
people but not in others, and the functional 5-
HTTLPR was found to moderate the influence of
stressful life events on depression. Individuals with
one or two copies of the S-allele exhibited more
depressive symptoms, diagnosable depression and
suicidality to stressful life events than individuals
being homozygous for the L-allele.199 In the majority
of the studies only one single polymorphism in one
gene was investigated, thus hardly being able to
uncover an interaction between the different factors
contributing to the liability for suicidality.
Despite these points of criticism there is no doubt
that genetic variants remain one of the multiple
factors implicated in the phenomenon of suicide
and represent a serious risk factor, in particular when
an individual is confronted with stress, such as
negative life events and somatic disorders. Thus,
further studies are needed to identify more robustly
the susceptibility genes using well-characterized
suicide phenotypes. Some genetic factors may be
related to aggressiveness and impulsivity, which have
their effects independently of, or additively to, a
mental disorder198 and the link to impulsive-aggres-
sive behaviour should be clarified.
Acknowledgments
A part of the work cited here was supported by the
German Federal Research Ministry within the promo-
tional emphasis Competence Nets in Medicine.
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