Directory UMM :Data Elmu:jurnal:B:Biological Psichatry:Vol48.Issue4.2000:

ORIGINAL ARTICLES
Serotonin Transporter Gene Polymorphisms,
Alcoholism, and Suicidal Behavior
Philip Gorwood, Philippe Batel, Jean Ade`s, Michel Hamon, and Claudette Boni
Background: Dysfunction of serotoninergic transmission
could predispose to excessive alcohol consumption and
dependence. The functional polymorphism of the serotonin
transporter gene (5-HTTLPR) has been associated with
different disorders, including alcoholism. Considering the
likelihood of heterogeneity in the “alcohol dependence”
phenotype, 5-HTTLPR may be more specifically implicated in subsamples of patients or in related traits of
alcoholism, such as impulsivity.
Methods: We analyzed the role of this functional polymorphism in the risk for suicide attempt in a population of
male alcohol-dependent subjects. One hundred ten male
alcohol-dependent patients (DSM-III-R criteria), French
for at least two generations, were personally interviewed
with the Diagnostic Interview for Genetic Studies and
compared with 61 unaffected blood donors.
Results: The “short” (S) allele of the 5-HTTLPR appeared to be unrelated to alcohol dependence and comorbid depression in our sample, but was found associated
with an increased risk for suicide attempts. This association was predominantly observed in severe and repetitive
suicide attempts, with a significant dose effect of the S

allele (0, 1, or 2) on the number and the severity of suicide
attempts.
Conclusions: Mood disorders and alcohol dependence
may interact with a genetic (relative) deficiency in serotonin reuptake, thereby increasing the risk for aggressive/
impulsive behaviors such as suicide attempts. Biol Psychiatry 2000;48:259 –264 © 2000 Society of Biological
Psychiatry
Key Words: Suicide, serotonin, genetics, behavior, impulsivity, addiction, dependence

Introduction

E

vidence has accumulated for the last years that serotonergic neurotransmission is involved in alcoholism
(McBride et al 1993; Sellers et al 1992). Thus alcohol-

From Service de Psychiatrie, Hoˆpital Louis Mourier (AP-HP), Colombes (PG, JA),
CNRS UMR 7593-Paris VII, Personnalite´ et Conduites Adaptatives, CHU
Pitie´-Salpeˆtrie`re, Paris (PG, JA), Hoˆpital Beaujon (AP-HP), UTAMA, Clichy
(PB), and INSERM U 288, Neuropsychopharmacologie, CHU Pitie´-Salpeˆtrie`re, Paris (MH, CB), France.
Address reprint requests to Philip Gorwood, M.D., Ph.D., CNRS UMR 7593, CHU

Louis Mourier, 178, rue des Renouillers, 92700 Colombes, France.
Received July 1, 1999; revised October 11, 1999; accepted February 2, 2000.

© 2000 Society of Biological Psychiatry

drinking behavior seems to be associated with low activity
levels of central serotonin (5-HT) systems (Ferreira and
Soares-Da-Silva 1991; LeMarquand et al 1994b; Zhou et
al 1994). Alterations in 5-HT uptake have also been
described in alcohol-dependent patients (Ernouf et al
1993; Heinz et al 1998) that may sustain such alcohol–
5-HT relationships because selective 5-HT reuptake inhibitors, such as fluoxetine, sertraline, and citalopram, regularly produce a decrease in alcohol craving and drinking in
alcoholic patients (Balldin et al 1994a, 1994b; Higley et al
1998; Lejoyeux 1996; Lu et al 1994; Naranjo et al 1994).
Alcoholic subjects are dramatically exposed to suicidal
behavior (Kessler et al 1994) and suicide mortality (Rossow and Amundsen 1995), which may also be causally
related to altered 5-HT neurotransmission. Indeed, low
levels of 5-HT and/or its metabolite 5-hydroxyindoleacetic
acid (5-HIAA) have regularly been found in blood and
cerebrospinal fluid (CSF) of subjects who attempted suicide (Pihl and LeMarquand 1998). Interestingly, alterations in 5-HT uptake have also been reported in these

subjects (Ellis and Salmond 1994; Meltzer et al 1981). The
interaction between alcoholism and 5-HT uptake may thus
be relevantly tested to explain the increased risk for
suicidal behavior in alcohol-dependent patients.
Polymorphism of the gene encoding the 5-HT transporter (5-HTT) notably concerns its promoter (Heils et al
1996). The region between base pair (bp) 1376 and bp
1027 contains 16 tandem repeats of a 20- to 23-bp G1C
rich sequence. Two common forms of this region were
found in a white population: a 528-bp allele with 16
repeats (“long” [L] allele) and a 448-bp allele (“short” [S]
allele) with a deletion of 44 bp extending from bp 1255 to
bp 1212. The 528-bp long allele of the 5-HTT promoter is
two- to threefold more active in driving transcription than
the 484-bp allele in transfection experiments (Heils et al
1996). In addition, 5-HT uptake is twice as high in
lymphoblastoid cells from individuals homozygous for the
528-bp allele as in cells from individuals of the other
genotypes (Lesch et al 1996). The potential role that this
functional polymorphism in the 5-HTT promoter may play
in personality traits and psychiatric diseases has already

been the matter of numerous studies; however, to date,
rather controversial data have been reported regarding a
possible association of either the short or the long allele
with sometimes mood disorders and sometimes anxiety0006-3223/00/$20.00
PII S0006-3223(00)00840-4

260

P. Gorwood et al

BIOL PSYCHIATRY
2000;48:259 –264

related disorders (Ball et al 1997; Bellivier et al 1997;
Collier et al 1996; Ewald et al 1998; Gutie´rrez et al 1998;
Jorm et al 1998; Kunugi et al 1997; Lesch et al 1996;
Matsushita et al 1997; McDougle et al 1998; Nakamura et
al 1997; Rees et al 1997).
Similarly, conflicting data have been reported about the
possible association of polymorphism of the 5-HTT gene

promoter with alcoholism. Thus, Sander et al (1998) and
Schmidt et al (1997) found that the frequency of the short
allele is significantly increased in alcoholic patients with
severe dependence as compared with nonalcoholic control
subjects. On the other hand, Tu¨rker et al (1998) noted the
existence of a significant association between the short
allele of the 5-HTT gene promoter and high ethanol
tolerance in young adults. In contrast, Edenberg et al
(1998) and Jorm et al (1998) could not find any association between polymorphism of the 5-HTT gene promoter
and alcohol misuse and dependence.
Because heterogeneity in the population of alcoholic
patients might have contributed to these discrepancies,
further investigations on a possible association between
this polymorphism and various subgroups of alcoholics
have been performed. Distinction of subgroups based on
the presence and type of suicidal behavior allowed the
discovery of a significant association between the presence of the short allele of the 5-HTT gene promoter and
severe suicide attempts in alcoholic-dependent patients.

Methods and Materials

Seventy male control subjects, recruited from a blood transfusion
center, were at least 35 years old and French for at least two
generations, without any substance dependence (DSM-III-R).
The age of 35 was considered as a cutoff to reduce the risk that
control subjects may lately develop alcohol dependence. Using
the same clinical instruments as for the patients, we eliminated
four subjects who fulfilled the DSM-III-R alcohol dependence or
abuse criteria, and three others because they made a suicide
attempt at least once in their life. In addition, two subjects
refused to participate. Finally, 61 control subjects were included
in this study.
We recruited 110 male alcoholics from two general hospitals
that specialize in the treatment of alcoholism, in Paris and its
suburbs. Inclusion criteria consisted of DSM-III-R criteria of
alcohol dependence, French origin for at least two generations,
and no comorbid dementia. Schizophrenia and bipolar manic–
depressive disorder were exclusion criteria. The lifetime psychiatric and addictive diagnoses were made by face-to-face interview using the Diagnostic Interview for Genetic Studies (DIGS;
Nurnberger et al 1994). The alcoholic patients were seen on
average at 43.6 years of age (SD 5 10.5), alcohol dependence
occurring on average at 26.0 years (SD 5 8.6). The average score

in the Michigan Alcoholic Screening Test (Selzer 1971, derived
from the DIGS) was 32.5 (SD 5 11.7). The psychiatric comorbidities were mainly major depressive disorder (N 5 27),

antisocial personality disorder (N 5 22), pathological gambling
(N 5 20), agoraphobia (N 5 19), other dependence such as for
cannabis (N 5 12), opiates (N 5 12), sedatives (N 5 11), and
cocaine (N 5 6). In this sample 181 suicides were attempted,
involving 55 patients. The degree of lethality (rated from 0 to 6
according to the DIGS) was “severe” in 13 patients (e.g., cut
throat) and “very severe” (with respiratory arrest or prolonged
coma) in two cases.
Genomic DNA was extracted from anticoagulated venous
blood samples (Loparev et al 1991). The serotonin transporter
gene (5-HTTLPR) of the 5-HTT gene regulatory region was
amplified (Heils et al 1996) by polymerase chain reaction with
oligonucleotide primers srtp5 (59-GGCGTTGCCGCTCTGAATGC-39) and srtp3 (59-GAGGGACTGAGCTGGACAACCAC-39). Polymerase chain reaction reactions were performed
with 50 ng genomic DNA, 10 pmol of each primer, 20 mmol/L
KCl, 10 mmol/L Tris-HCl (pH 8.8), 16 mmol/L (NH4)2SO4,
0.01% Tween 20, 1.5 mmol/L MgCl2, 200 mmol/L of deoxynucleotides, 5% dimethyl sulfoxide, and 1 unit of Eurobiotaq
polymerase, in a total volume of 25 mL.

Cycling conditions were preceded by a denaturation step at
85°C for 20 min, followed by 35 cycles of denaturation at 95°C
for 1 min, annealing at 61°C for 1 min, and synthesis at 72°C for
1 min. Amplification products were separated by electrophoresis
in a 2% agarose gel and visualized by UV after ethidium bromide
staining. The 484-bp fragment of the biallelic polymorphism was
designated as “S” and the 528-bp fragment as “L.” Genotyping
was carried out blindly, without knowledge of the diagnostic
status.
Allele and genotype frequencies were compared with x2 tests,
and the test for Hardy–Weinberg equilibrium was performed for
each sample. Linear trend in variation of frequencies of the
involved allele with respect to the number (or severity) of suicide
attempts was evaluated with the Armitage test (Armitage 1955).
Because of the quantitative impact of the S allele on the
transcription level (Heils et al 1996) of the 5-HTT gene (subjects
with at least one S allele having less 5-HTT binding sites and
messenger RNA in the midbrain than homozygous “LL” subjects
[Little et al 1998]), nonparametric correlation analyses (Spearman test) were performed (with the appropriate corrections for
equal values) between quantitative variables and the number of S

allele (0, 1, or 2). The impact of mood disorders in the relation
found between “5-HTT polymorphisms” and “suicide attempts”
was analyzed through an analysis of variance.

Results
No difference in genotype counts was found between
alcoholics and control subjects [x2(2) 5 1.61, p 5 .45].
The same conclusion applied between subjects with or
without the S allele [x2(2) 5 1.54, p 5 .21]. Both control
subjects and alcohol-dependent patients were in accordance with Hardy–Weinberg equilibrium for the polymorphisms tested [respectively, x2(1) 5 0.7, p 5 .39 and
x2(1) 5 0.1, p 5 .55].
The frequencies of 5-HTTLPR genotypes containing
the short variant (“LS” and “SS”) were 60.6% in control

Alcoholism, Suicidal Behavior, and 5-HTT Gene

Table 1. Genotype Counts of Polymorphism within the
Serotonin Transporter (5-HTT) Promoter in Alcoholic Patients
(with or without Suicide Attempts) and Unaffected Matched
Control Subjects

Table 2. Number of “Short” (S) Allele (Serotonin Transporter
Gene Polymorphism) According to the Existence of Suicide
Attempts and Lifetime Diagnosis of Depressive Disorder in
110 Alcohol-Dependent Patients

Alcohol-dependent subjects
Control
subjects

Without suicide
attempt

261

BIOL PSYCHIATRY
2000;48:259 –264

Lifetime major depressive (MD) disorder

With suicide
attempt

With MD
(no. of S allele)

Without MD
(no. of S allele)

5-HTTLPR
genotypes

N

(%)

N

(%)

N

(%)

Suicide attempt

0

1

2

0

1

2

LL
LS
SS

24
26
11

39.3%
42.6%
18.0%

21
26
8

38.2%
47.3%
14.5%

12
30
13

21.8%
54.5%
23.6%

With
Without

0
6

11
4

5
1

12
15

19
22

8
7

Genotype counts are not significantly different in alcohol-dependent patients
and control subjects [x2(2) 5 1.61, p 5 .45]. Genotypes with the “short” (s) allele
(LS and SS) are more frequent in alcohol-dependent patients with suicide attempt
(78.1%) than in alcohol-dependent patients without suicide attempt [61.8%; x2(1)
5 3.51, p 5 .06] and control subjects [60.6%; x2(1) 5 4.15, p 5 .04].

subjects (without suicidal behavior), 61.8% in alcoholics
without suicidal behavior, and 78.2% in alcoholics who
tried at least once to commit suicide (Table 1). Thus,
alcoholics with suicidal behavior have different genotypes
than normal control subjects and a tendency for different
genotypes than alcoholics with no history of suicidal
behavior (Table 1).
Number and lethality of suicide attempts were then
compared between alcoholic patients according to the
presence of the short variant of the 5-HTT gene promoter.
We noted a regular increase in the frequency of the S allele
with the number of suicide attempts for each subject:
61.8% for patients with no suicide attempt, 74.2% for
patients who committed a suicide attempt once or twice,
82.3% for those who tried three or four times, and 83.3%
for patients with more than four suicide attempts. The
linear trend for increased S allele frequency according to
the number of suicide attempts (none, once or twice, three
or four times, and more than four) was significant [x2(1) 5
3.89, p 5 .05, Armitage test]. Furthermore, a “dose effect”
of the S allele was observed, with a significant positive
correlation between the number of suicide attempts and
the number of the S allele (0, 1, or 2; r 5 .193, p 5 .04).
We also observed an increase in the presence and the
frequency of the S allele in alcohol-dependent patients
according to the lethality of suicide attempts. Sixty-two
percent of patients with no suicide attempt (N 5 55) had
the S allele; this percentage increased to 78% for patients
with moderate lethality suicide attempts (N 5 40) and to
80% for those with more severe suicide attempts (N 5 15).
In this last group, the two patients with very severe suicide
attempts both had the S allele. In this view, we found a
significant increase in the S allele frequency according to
the lethality of suicide attempts [i.e., no suicide attempt, at
least a suicide attempt, at least one severe suicide attempt,
and at least one very severe attempt; x2(1) 5 4.41, p 5
.04, Armitage test]. A dose effect of the S allele was also

Analysis of variance: major depression effect [F(1,106) 5 0.02, p 5 .89],
suicide attempt effect [F(1,106) 5 6.83, p 5 .01], interaction between major
depression and suicide attempt [F(1,106) 5 3.74, p 5 .05].

observed, as there is a correlation between the degree of
lethality of suicide attempts and the number of the S allele
(0, 1, or 2; r 5 .185, p 5 .05).
Comorbid depression might explain increased suicide
attempts in samples of alcohol-dependent subjects. In our
sample, the two variables “existence of at least one major
depression episode” and “at least one suicide attempt”
were significantly interacting with the number of the S
allele (Table 2). Taking into account this interaction, we
found a significant impact of 5-HTTLPR polymorphisms
on suicide attempts alone, but not on major depression
alone. For example, in this sample 76.2% of alcoholdependent patients with the S allele and with lifetime
comorbid major depressive disorder (N 5 21) made at
least one suicide attempt. On the other hand, only 44.4%
of patients with no S allele and no comorbid lifetime major
depression disorder (N 5 27) made a suicide attempt
[x2(1) 5 5.46, p 5 .02].

Discussion
For the sample studied, no association could be found with
5-HTTPR polymorphisms and alcohol dependence per se, in
agreement with most recent studies (Edenberg et al 1998;
Jorm et al 1998). Accordingly, it can be inferred that the
changes in 5-HT reuptake capacity in alcoholic patients that
were noted in previous studies (Ernouf et al 1993; Heinz et al
1998) do not probably reflect changes in expression of the
5-HTT– encoding gene that would depend on the presence of
the S or L allele promoter. Indeed, opposite changes in 5-HT
reuptake—that is, an increase in platelets (Ernouf et al 1993)
versus a decrease in brain (Heinz et al 1998)— have been
reported in alcoholic patients, strongly suggesting that these
changes are independent of the 5-HTT gene promoter but are
related to local environmental conditions, affecting 5-HTT
functioning differently in the periphery versus in the central
nervous system. Furthermore, postmortem studies showed
that the density of 5-HTT binding sites in the midbrain of
alcoholic subjects was significantly higher than that in con-

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2000;48:259 –264

trol subjects with the same SS or SL genotypes, in line with
the hypothesis that alcohol consumption per se can affect the
5-HTT at postranscriptional level(s) (Little et al 1998).
Interestingly, further phenotypic definition of alcoholic
patients led to the distinction of alcohol-dependent subjects with dissocial personality disorder for whom a
significant association was found between the presence of
the S allele of the 5-HTT gene promoter and a temperamental profile of high novelty seeking and low harm
avoidance (Edenberg et al 1998). In the present sample,
analysis of various phenotypic parameters revealed that
other subgroups could be identified within the alcoholic
population, depending on both a history of suicide attempts and the presence of mood disorders.
First, we found that in the recruited alcohol-dependent
patients the risk for suicidal behavior and, particularly, for
repeated suicide attempts and attempts with high lethality
is partly dependent on 5-HTTLPR polymorphisms. In our
sample, the S allele is qualitatively distinguishing patients
with or without suicide attempts and is quantitatively
correlated to number and severity of suicide attempts.
The second result of our study is that comorbid mood
disorder is significantly interacting with 5-HTTLPR polymorphisms to “explain” suicide attempts in alcohol-dependent patients. It is the interaction that is involved and not
mood disorder per se, as 5-HTTLPR polymorphisms are
not associated with depression in our sample. These results
are consistent with those of Bellivier et al (2000) showing
no direct impact of 5-HTTLPR on recurrent mood disorder, but a significant impact of the S allele on suicide
attempts, especially for those with high lethality.
Long-term, prospective studies of psychiatric patients
have shown that affective disorder and alcoholism are
most frequently found in suicidal cases. Thus, Robins
(1981) reported that of 134 subjects who committed
suicide, 47% were suffering from depression and 25%
from alcoholism. Similarly, in their study Barraclough et
al (1974) noted that most patients among 100 suicide cases
were suffering from either depression (70%) or alcoholism
(15%). Furthermore, the most prevalent psychopathology
among alcoholics who commit suicide is affective disorder
(Berglund 1984; Cornelius et al 1995; Murphy et al 1979;
Whitters et al 1985).
Acute alcohol intake transiently increases central 5-HT
functioning, whereas chronic intake decreases it (LeMarquand et al 1994a). Chronic alcohol intake may lead to a state
of lowered central 5-HT functioning characterized by a
propensity toward disinhibited behavior, thus increasing the
potential for aggressive behavior (Pihl and LeMarquand
1998). When expressed towards the self (suicide), aggressive
behavior has been associated with low CSF levels of the
5-HT metabolite 5-HIAA regardless of diagnosis (TraskmanBendz et al 1986; Tuinier et al 1995; van Praag 1983), this

P. Gorwood et al

relationship being particularly significant for violent suicide
(Asberg et al 1976). It is the severity and impulsivity of
suicide that may thus be related to low 5-HT functioning. On
the other hand, depression per se is also associated with
reduced 5-HT neurotransmission, as evidenced by low CSF
5-HIAA levels (Meltzer and Lowy 1987) and plasma free
tryptophan levels (Coppen and Wood 1978; DeMeyer et al
1981) in depressed patients. The existence of a causal
relationship between depression and reduced 5-HT neurotransmission is strongly supported by the observation that
tryptophan depletion (which efficiently decreases central
5-HT synthesis [Nishizawa et al 1997]) can produce a
lowering of mood both in normal subjects and in recovered
depressed patients (Benkelfat et al 1994; Salomon et al 1993;
Smith et al 1997).
In our sample, the S allele, leading to lower 5-HT
transport capacity than the L allele (Heils et al 1996), is
associated with an increased risk of suicide attempts, this
association being stronger for numerous suicide attempts
with high lethality. Variation of the S allele frequency
according to number and severity of suicide attemps could
be interpreted in two ways. First, the impact of the S allele
could be associated with the aggressive/impulsive dimension, which is probably (quantitatively) increased in severe
suicide attempts. Another explanation is that the (qualitative) presence of nonviolent, nonimpulsive suicide attempts (e.g., pill ingestion) is probably reduced in more
severe suicide attempts.
The impact of the S allele is also especially significant
when lifetime comorbid depression is present, and when
suicide attempts are characterized by frequent antecedents
and severe lethality. Mood disorders and alcohol dependence may interact with a genetic (relative) deficiency in
5-HT reuptake, thereby increasing the risk for aggressive/
impulsive behaviors such as suicide attempts.
Some limitations have to be raised in this study,
however, notably regarding the limited size of our sample.
The main analyses are based on the comparison of two
groups of 55 subjects each, but some subsamples, such as
those with severe suicide attempts (N 5 15), are of limited
size, especially as interaction between different variables
has been tested. Although very similar results have been
found in Bellivier and colleagues’ study (2000)—namely,
the S allele is not increasing the risk for any specific
psychiatric disorder, but instead is associated with suicide
behavior— other replications have to be made on larger
samples of alcohol-dependent subjects.

This work was promoted by INSERM (No. 339), with the grants of
INSERM (re´seau 494001), AP-HP (No. CRC-94038), MGEN, and IREB
(No. 9303-9718-9719).

Alcoholism, Suicidal Behavior, and 5-HTT Gene

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