Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology

Behavioral Sciences and the Law

Behav. Sci. Law 22: 415–425 (2004)

Published online in Wiley InterScience (www.interscience.wiley.com). DOI: 10.1002/bsl.589

RESEARCH REPORT

Association of SerotoninTransporter Promoter GenePolymorphism with Violence:Relation with PersonalityDisorders, Impulsivity, andChildhood ADHDPsychopathology

Wolfgang Retz, M.D.,1* Petra Retz-Junginger,Ph.D.,1 Tillmann Supprian, M.D.,2

Johannes Thome, M.D., Ph.D.3

and Michael Rosler, M.D.1

There is evidence that disturbances in central serotonin

(5-HT) function have a role in impulsive aggression, vio-

lence, and criminality. A deletion/insertion polymorphism

within the 5-HT transporter (5-HTT) promoter gene

(5-HTT gene-linked polymorphic region, 5-HTTLPR) is

thought to be associated with several psychopathological

phenotypes related to disturbed impulse control, anxiety

and depression. This study examined the association of the

5-HTTLPR with violent behavior in a sample of 153 male

Caucasians referred for a forensic psychiatric examina-

tion. We found a significant excess of the short (s) allele

and the s/s genotype in patients characterized by recurrent

and overt physical violent behavior. This genetic variance

explained 5% of the variance of violent behavior.

When controlled for the impact of several psychopatho-

logies related to violent behavior, this association was

observed in individuals with a history of childhood attention

deficit/hyperactivity disorder (ADHD)-related symptoms,

but not presenting with personality disorder or increased

impulsiveness. In conclusion, the results (i) suggest an

association between serotonergic dysfunction and violent

Copyright # 2004 John Wiley & Sons, Ltd.

*Correspondence to: Wolfgang Retz, M.D., Institute for Forensic Psychology and Psychiatry, Universityof the Saarland, D-66421 Homburg/Saar, Germany. E-mail: [email protected] for Forensic Psychology and Psychiatry, University of the Saarland, Homburg/Saar, Germany2The Saarland University Hospital, Department of Psychiatry, Homburg/Saar, Germany3Central Institute of Mental Health, Mannheim, Germany

behavior, (ii) provide evidence for an—at least partial—

genetic regulation of violent behavior in a subgroup ofmale

offenders, and (iii) suggest a significant role for 5-HT

transporter functionality for violent behavior. Copyright

# 2004 John Wiley & Sons, Ltd.

An extensive literature supports the notion that neurobiological mechanisms are

involved in human aggression and violence (Berman & Coccaro, 1998; Filley

et al., 2001; Volavka, 1999). Several lines of evidence suggest that disturbances in

central serotonin (5-HT) function may play a role in violent behavior. Associations

between 5-HT dysfunction and interpersonal aggression, suicide attempts and

impulse control, respectively, have been shown in patients with a wide range of

psychiatric diagnoses. In neurochemical studies low cerebrospinal fluid concentra-

tions of 5-hydroxyindolacetic acid have been found to be related to impulsive

aggressive and violent behavior in offenders and psychiatric patients (Brown et al.,

1982; Kruesi et al., 1990; Lidberg, Tuck, Asberg, Scalia-Tomba, & Bertilsson,

1985; Linnoila et al., 1983; Virkkunen et al., 1994). Also, platelet binding studies

(Birmaher et al., 1990; Brown et al., 1989; Coccaro, Kavoussi, Sheline, Lish, &

Csernansky, 1996) and pharmacological challenge trials (Cherek, Moeller, Khan-

Dawood, Swann, & Lane, 1999; Coccaro et al., 1997; Dolan, Anderson, & Deakin,

2001; O’Keane et al., 1992) have supported the impression of decreased serotonin

functioning in violence and aggressivity. Moreover, a negative association between

aggression/delinquency and monoamino oxidase activity has been observed

(Belfrage, Lidberg, & Oreland, 1991; Schalling, Asberg, Edman, & Oreland,

1987). These findings indicate that reduced 5-HT functioning is possibly related

to a general trait of impulsiveness, aggressiveness, and violent behavior, rather than

to a specific diagnostic entity (Coccaro, Kavoussi, & Lesser, 1992).

There is increasing evidence that violent aggression, criminality, and antisocial

behavior are partially determined by genetic factors (Brennan, Mednick, & Jacobsen,

1996; Miles & Carey, 1997). In male individuals, specific candidate genes involved in

various neurotransmitter systems have been linked in some but not all studies with

these phenotypes. Associations with serotonergic genes have been described for

suicide (Abbar et al., 2001; Arias et al., 2001; Bondy, Erfurth, de Jonge, Kruger, &

Meyer, 2000; Courtet et al., 2001; New et al., 2001) and also for several other

psychiatric disorders related to a general lack of impulse control, antisocial person-

ality, and impulsive aggression, such as addiction (Hallikainen et al., 1999; Hwu &

Chen, 2000; Lappalainen et al., 1998; Nakamura et al., 1999; Preuss, Koller, Soyka,

& Bondy, 2001; Sander et al., 1998), eating disorders (Levitan et al., 2001) and

attention deficit/hyperactivity disorder (ADHD) (Manor et al., 2001; Retz, Thome,

Blocher, Baader, & Rosler, 2002; Seeger, Schloss, & Schmidt, 2001).

The human 5-HT transporter gene has been shown to contain a common

functional insertion/deletion polymorphism in the upstream promoter region.

This promoter polymorphism is biallelic, with a short (s) and a long (L) allele.

Several studies have demonstrated a higher transcriptional activity of the L-allele

under in vitro conditions (Heils et al., 1996). Compared with the s/s and the s/L

genotype, serotonin uptake by cells homozygous for the L form of the promoter

polymorphism is about two fold higher. Carriers of the s allele exhibit blunted

416 W. Retz et al.

Copyright # 2004 John Wiley & Sons, Ltd. Behav. Sci. Law 22: 415–425 (2004)

central 5-HT function as measured by fenfluramine-induced prolactin release

(Reist, Mazzanti, Vu, Tran, & Goldman, 2001).

Only a few studies concern a possible relation between the 5-HT transporter

promoter gene polymorphism and violence. Zalsman and coworkers have reported a

significant difference in violence measures in suicidal patients carrying the L/L and

L/s genotypes (Zalsman et al., 2001). In a study concerning homicidal behavior in

schizophrenics, no association was observed with the 5-HT transporter promoter

gene polymorphism (Kotler et al., 1999). The present study was performed in order

to further elucidate the relationship between the 5-HT transporter promoter

genotype and violent behavior, antisocial personality disorder, and a history of

childhood ADHD symptomatology in a sample of offenders.

MATERIALS AND METHODS

Subjects

A sample of 153 consecutively recruited, adult male volunteers, who were referred to

the Forensic-Psychiatric Institute of the University of Saarland Homburg/Saar,

Germany for a forensic examination, entered the study after providing informed

consent. They included 132 criminal defendants and 21 individuals who were

examined for civil law issues, such as driving ability (n¼ 21). Mean age was 34.7

years (SD 11.1 years, range 16–70 years). To avoid stratification effects in this genetic,

case–control study, only Caucasians and no relatives of subjects were included.

Subjects were assigned to a violent and a nonviolent group according to their

history of criminal charges based on a careful evaluation of all available documents

(Figure 1). For this study, violence was defined as ‘‘overt and intentional physically

aggressive behavior against another person’’ according to the concept used by

Volavka (1999) and accepted by expert consensus (Filley et al., 2001).

Figure 1. Criminal charges and numbers of violent and nonviolent offenses in the study population.

Association of 5-HTTLPR with violence 417


All participants underwent psychiatric and neurological evaluations and standard-

ized psychometric tests. These included the Eysenck Impulsiveness Questionnaire

(EIQ) and the German short form of the Wender Utah Rating Scale (WURS-k). The

EIQ was applied to measure impulsiveness, venturesomeness, and empathy

(Eysenck, Daum, Schugens, & Diehl, 1990). The EIQ consists of 54 items rated

‘‘yes’’ or ‘‘no’’, and the scores for the impulsiveness subscore range from 0 to 17. The

German short form of the Wender Utah Rating Scale (WURS-k) was used for the

assessment of ADHD-related symptomatology in childhood, namely attention

problems, emotional instability, oppositional/defiant behavior, and social maladapta-

tion (Retz-Junginger et al., 2002). The WURS-k is a 25-item retrospective, dimen-

sional measure of symptoms associated with childhood ADHD, based on the widely

used Utah criteria for the diagnosis of ADHD and the original version of the Wender

Utah Rating Scale (Wender, 1995). It has been shown that sensitivity and specificity

of the WURS-k for detection of childhood ADHD in males were 85 and 76%,

respectively, when a cut-off score of 30 was used (Retz-Junginger et al., 2003).

Psychiatric diagnoses were determined according to ICD 10 criteria, using

modified, standardized checklists (Hiller, Zaudig, & Mombour, 1990) by well

trained psychiatrists.

Genotyping

Polymorphisms in the promoter region of the 5-HT transporter gene were deter-

mined after extraction of genomic DNA from venous blood samples following

standard procedures. DNA amplification was performed using a well established

polymerase chain reaction procedure (PCR) as described elsewhere in detail (Lesch

et al., 1996). For PCR two oligonucleotide primers flanking the polymorphic gene

region were used (50-GGC GTT GCC GCT CTG AAT GC-30 and 50-GAG GGA

CTG AGC TGG ACA ACC A-30). These short segments of DNA bind to the

denaturated DNA template (the DNA segment to be amplified by the PCR

reaction) to provide an initiation site for the elongation of the new DNA molecule

(annealing and extension). The PCR process consisted of a five minute denaturation

step at 94�C, 40 cycles of 30 second denaturation at 94�C, 30 second annealing at

63�C, and 60 second extension at 72�C, and a final ten minute extension step at

72�C. PCR products (amplified DNA containing the long or the short alleles in

homozygous individuals, or both alleles in heterozygous individuals) were separated

by electrophoresis in a 3% agarose gel stained with ethidium bromide. The long and

the short alleles were defined by specific bands on the agarose gel, which were

visualized by UV transillumination of the gel.

Statistical Analyses

All statistical evaluations were performed with SPSS for Windows. The genotypic

distribution between groups was compared using �2- and Fisher’s exact tests,

respectively. The allele frequencies were calculated according to the gene counting

method. Eta squared was calculated using one-way analysis of variance (ANOVA)

to estimate the magnitude of variance accounted for by genotype.

418 W. Retz et al.


Non-parametric correlations between genotypes, impulsivity measures (EIQ)

and assessment of ADHD-related psychopathology (WURS-k) were calculated

using the Kruskal–Wallis test.

RESULTS

Forty-two (27.5%) subjects of the entire group had no psychiatric Axis I or II

diagnosis; 65 (42.4%), one diagnosis; and 46 (30.1%), two or more diagnoses.

Frequencies of diagnostic categories according to ICD10 criteria are given in

Figure 2. As expected in a forensic population, personality disorders were very

common (24.7%). Antisocial personality disorder was the most frequent personality

disorder diagnosed (10.7%), whereas 14.0% of the patients suffered from another

personality disorder. A significant association was found between violence and

antisocial personality disorder (�2¼ 5.499; p¼ 0.019), but not with other personality

disorders. There were also no significant associations between violence and impul-

siveness scores on the EIQ and scores on the WURS-k using non-parametric statistics.

Moreover, the frequencies of substance use disorders (SUDs) in the violent and

nonviolent groups were not statistically different (48.6% and 41.9%, respectively).

In the entire population the distribution of the three genotypes s/s: s/L: L/L was

15.7%: 57.5%: 26.8%. The frequency of the s allele was 44% and that of the L allele

56%. Genotype and allele frequencies for the 5-HT promoter gene polymorphism

are shown in Table 1 for 81 nonviolent and 72 violent individuals. Overall, a

Figure 2. Number of diagnoses of the patients (n¼ 153), according to the diagnostic categories ofICD10. Forty-six patients had more than one diagnosis. F00–F09 Organic, including symptomatic,mental disorders; F10–F19 Mental and behavioral disorders due to psychoactive substance use; F20–F29Schizophrenia, schizotypal and delusional disorders; F30–F39 Mood (affective) disorders; F40–F48Neurotic, stress-related and somatoform disorders; F50–F59 Behavioral syndromes associated withphysiological disturbances and physical factors; F60–F69 Disorders of adult personality and behavior;

F70–F79 Mental retardation.



significant difference was observed in genotype frequencies between the two groups

(�2¼ 8.19, p¼ 0.01). A significant excess of the s allele was observed in the violent

group compared to the nonviolent group (�2¼ 6.43; p¼ 0.01). There were sig-

nificantly more carriers of at least one s allele in the violent patient group (violent, s/s

and s/L, 80.6%; L/L, 19.4%; nonviolent, s/s and s/L, 66.7%; L/L, 33.3%; �2¼ 3.75,

p¼ 0.05). Prevalence of the s/s genotype was 23.6% in the violent group and 8.6% in

the nonviolent group in comparison with 76.4% and 91.4% for the s/L and L/L

genotypes (�2¼ 6.46, p¼ 0.01).

Using a one-way ANOVA, the 5-HTT promoter gene polymorphism explained

5.0% (eta squared¼ 0.50) of the variance of the patients’ violence.

Subsequently, we analysed the impact of personality disorders, impulsivity

measures, and a history of ADHD-related psychopathology on the genotype

distribution within the violent and the nonviolent groups. The groups of violent

and nonviolent individuals were dichotomized according to the diagnosis of a

personality disorder, high impulsivity (EIQ score>11, which is two SDs above

the mean score of the entire study population), and a history of ADHD, assumed by

high ratings on the WURS-k (score �30) (Table 2). A significant overrepresenta-

tion of the s/s genotype and the s allele, respectively, in the violent group, was

Table 1. 5-HTTLPR genotype and allele frequencies of the nonviolent and the violent patient groups.Significantly different distributions between the groups were found according to genotypes (a�2¼8.19;

p¼0.017) and allele frequencies (b�2¼ 6.43; p¼ 0.01)

Nonviolent (n¼81) Violent (n¼72)

s/s 7 (8.6) 17 (23.6)s/L 47 (58.0) 41 (56.9)LL 27 (33.3) 14 (19.4)a

f(s) 0.375 0.521f(L) 0.625 0.479b

Table 2. 5-HTTLPR genotype and allele frequencies of violent and nonviolent patients according tocurrent diagnosis of antisocial personality disorder, high impulsiveness measures (EIQ score 2 SDsabove mean score), and history of ADHD-related psychopathology (WURS-k�30). A significant excessof the s/s genotype and s allele in the violent group was observed in absence of antisocial personalitydisorder (a�2¼7.25, p¼ 0.02, and b�2¼5.05, p¼ 0.02, compared to nonviolent individuals), andnormal EIQ measures of impulsiveness (c�2¼ 8.77, p¼0.01, and d�2¼ 7.01, p¼ 0.01, compared tononviolent individuals). Violent individuals with a childhood history of ADHD-related symptomatologyshowed a significantly higher frequency of the s/s genotype and the s allele compared with the nonviolent

group (e�2¼5.79, p¼ 0.05, and f�2¼ 5.11, p¼ 0.02)

Personality High Childhood ADHD-relateddisorder impulsiveness symptomatology

No (n¼ 113) Yes (n¼37) No (n¼ 115) Yes (n¼29) No (n¼93) Yes (n¼53)

Nonviolent s/s 5 (7.8%) 2 (13.3%) 5 (8.8%) 2 (10.5%) 6 (12.2%) 1 (3.6%)s/L 40 (62.5%) 5 (33.3%) 34 (59.6%) 10 (52.6%) 32 (65.3%) 13 (46.4%)L/L 19 (29.7%) 8 (53.3%) 18 (31.6%) 7 (36.8%) 11 (22.4%) 14 (50.0%)f(s) 0.391 0.300 0.386 0.368 0.449 0.268f(L) 0.609 0.700 0.614 0.632 0.551 0.732

Violent s/s 12 (24.5%) 5 (22.7%) 16 (27.6%) 1 (10.0%) 11 (25.0%) 6 (24.0%)s/L 29 (59.2%) 12 (54.5%) 33 (56.9%) 5 (50.0%) 26 (59.1%) 12 (48.0%)L/L 8 (16.3%)a 5 (22.7%) 9 (15.5%)c 4 (40.0%) 7 (15.9%) 7 (28.0%)e

f(s) 0.541 0.500 0.560 0.350 0.545 0.480f(L) 0.459b 0.500 0.440d 0.650 0.455 0.520f

420 W. Retz et al.


observed in the subgroups without personality disorders and low impulsiveness

measures, but not in the groups with personality disorders and high impulsiveness.

Concerning the impact of personality disturbances, the same result was observed

when analyses where limited to antisocial personality disorders (�2¼ 7.32;

p¼ 0.02). However, the small number of individuals (n¼ 19) does not permit an

appropriate interpretation of this effect.

In individuals with a history of ADHD psychopathology, the s allele was

significantly more frequent in the violent group compared to nonviolent individuals,

but did not exceed the frequency of the L allele. No differences in mean ages were

found between the ADHD and the non-ADHD groups (33.3 years versus 35.9

years), suggesting that the associations found were not biased by age.

DISCUSSION

We found a significant association between the 5-HT transporter promoter gene

polymorphism and violent behavior. The results support the notion of disturbed

serotonergic functioning related to violence and aggressivity (Coccaro et al., 1992).

In particular, we found a significant overrepresentation of the short variant (s allele)

of the 5-HT transporter promoter gene and the s/s genotype in violent individuals.

The results conversely suggest a low prevalence of violent behavior in offenders, who

are hetero- or homozygous for the long 5-HTTLPR variant. This finding is—at

least partially—in accordance with some studies, which observed a link of the s allele

with violent suicide (Bondy et al., 2000; Courtet et al., 2001) and with habitually

impulsive violent behavior in alcoholics (Hallikainen et al., 1999). The results also

correspond to the association between the s allele and Neuroticism, a personality

trait defined as proneness to negative emotionality including hostility, and decreased

Agreeableness, a dimension reflecting expression of a spectrum of traits ranging

from cooperativeness to aggressiveness, originally reported by Lesch and coworkers

(Lesch et al., 1996; Lesch & Merschdorf, 2000).

Since many of the subjects reported childhood psychopathology related to

ADHD and there was a high prevalence of antisocial and other personality disorders

in this sample, the question arises of whether the 5-HT promoter gene polymorph-

ism is associated with violence per se or with ADHD or antisocial personality

disorder. Indeed, we found a significantly higher frequency of the s allele in violent

compared to nonviolent individuals with a childhood history of ADHD-related

psychopathology. Nevertheless, there was still a slight excess of the L allele in these

patients. This finding is consistent with recent studies that have demonstrated an

overrepresentation of the long allele of the 5-HT transporter promoter gene region

in ADHD (Manor et al., 2001; Retz et al., 2002; Seeger et al., 2001). This result

may suggest that the 5-HTTLPR L allele is associated with ADHD and carriers of

the L genotype have a higher risk for legal problems from ADHD psychopathology,

but a lower risk for violent criminal offences. However, this conclusion must await

large epidemiological studies.

The association of the L allele with nonviolent legal problems did not depend on

the diagnosis of antisocial or other personality disorders, which were the most

common psychiatric diagnoses in the entire population investigated, or on the

personality trait of high impulsiveness. Although there was an expected association



between violence and antisocial personality disorder, these results support a

relationship between the 5-HT transporter promoter gene polymorphism and

violent behavior rather than antisocial personality disorder.

As expected, there was a high prevalence of substance use disorders (SUDs) in

the study population. Since frequencies of SUD diagnoses did not differ between

the violent and the nonviolent groups, it is unlikely that the association between 5-

HTTLPR and violence was biased by SUD comorbidity. Regarding influence of

substances while subjects were violent, reliable information was not always avail-

able, hence we could not control for and rule out the possible direct effects of

chemical substances.

In our study the allelic distribution in the entire study population was very similar

to that described by Lesch et al. (1996) for a large sample of Caucasians. However,

there was a somewhat lower prevalence of individuals homozygous for the s allele in

our forensic males (15.7% versus 19%). It must be noted that no general population

controls were included in the study. Therefore, our study results must be interpreted

cautiously, because stratification effects cannot be ruled out.

Another limitation of our study is the operationalization of violence as aggressive

acts that cause physical injury. It should be emphasized that every attempt to

investigate violent behavior depends heavily on the construct validity of violence.

Violent behavior is heterogeneous, since violent acts differ in their origins, mechan-

isms, and management. In this study we relied on Volavka’s (1999) definition of

violence as ‘‘overt and intentional, physically aggressive behavior against another

person’’, accepted by expert consensus (Filley et al., 2001). Although analysis of

human aggression has revealed a consistent distinction between an impulsive–

reactive–hostile–affective subtype and a controlled–proactive–instrumental–preda-

tory subtype (Barratt, Stanford, Dowdy, Liebman, & Kent, 1999; Vitiello & Stoff,

1997), we did not differentiate types of violent behavior in this study. Further

studies regarding assessment of impulsive versus premediated aggression are needed

to elucidate more specifically the role of the 5-HTTLPR in aggressive and violent

behavior.

It is not clear exactly how the s allele alters serotonergic functioning and

contributes to phenotypic violence. Pharmacological studies with selective inhibi-

tors of 5-HT reuptake (SSRIs) and research on 5-HTT knockout mice suggest that

blunted 5-HT uptake and the resulting increase of synaptic 5-HT may cause

desensitization of various postsynaptic 5-HT receptors or stimulate presynaptic

autoreceptor activity, which could lead to down-regulation of 5-HT release

(Coccaro et al., 1996; Gobbi, Murphy, Lesch, & Blier, 2001; Raap & van de Kar,

1999). Moreover, the possibility of compensatory modifications in other neuro-

transmitter systems must be considered. Beside these effects in the adult brain,

crucial roles for both 5-HT and 5-HTT in the developing brain must be considered

(Gould, 1999). Transient expression of the 5-HTT gene in rat brains has been

demonstrated (Hansson, Mezey, & Hoffman, 1999), suggesting that 5-HTTLPR-

modulated gene expression during brain development may result in differences in

personality traits during adult life. From this point of view, therapeutic effects of

drugs interacting with the 5-HTT in adult violent offenders are not expected to

depend on the individual’s 5-HTTLPR genotype.

It is important to stress that the 5-HT transporter promoter gene polymorphism

accounts only for 5% of the violent behavior observed in the investigated

422 W. Retz et al.


population. Therefore, it should be emphasized that the contribution of the s allele

to any one individual’s proclivity to violence is very small. Nevertheless, this study

provides a rationale for further investigation of the genetic basis for violent behavior,

as well as for potential therapeutic effects of drugs that interact with the serotonergic

system.

REFERENCES

Abbar, M., Courtet, P., Bellivier, F., Leboyer, M., Boulenger, J. P., Castelhau, D., Ferreira, M.,Lambercy, C., Mouthon, D., Paoloni-Giacobino, A., Vessaz, M., Malafosse, A., & Buresi, C. (2001).Suicide attempts and the tryptophan hydroxylase gene. Molecular Psychiatry, 6, 268–273.

Arias, B., Gasto, C., Catalan, R., Gutierrez, B., Pintor, L., & Fananas, L. (2001). The 5-HT(2A)receptor gene 102T/C polymorphism is associated with suicidal behavior in depressed patients.American Journal of Medical Genetics, 105, 801–804.

Barratt, E. S., Stanford, M. S., Dowdy, L., Liebman, M. J., & Kent, T. A. (1999). Impulsive andpremeditated aggression: A factor analysis of self-reported acts. Psychiatry Research, 86, 163–173.

Belfrage, H., Lidberg, L., & Oreland, L. (1991). Platelet monoamine oxidase activity in mentallydisordered violent offenders. Acta Psychiatrica Scandinavica, 85, 218–221.

Berman, M. E., & Coccaro, E. F. (1998). Neurobiologic correlates of violence: Relevance to criminalresponsibility. Behavioural Sciences and the Law, 16, 303–318.

Birmaher, B., Stanley, M., Greenhill, L., Twomey, J., Gavrilescu, A., & Rabinovich, H. (1990). Plateletimipramine binding in children and adolescents with impulsive behavior. Journal of the AmericanAcademy of Child and Adolescent Psychiatry, 29, 914–918.

Bondy, B., Erfurth, A., de Jonge, S., Kruger, M., & Meyer, H. (2000). Possible association of the shortallele of the serotonin transporter promoter gene polymorphism (5-HTTLPR) with violent suicide.Molecular Psychiatry, 5, 193–195.

Brennan, P. A., Mednick, S. A., & Jacobsen, B. (1996). Assessing the role of genetics in crime usingadoption cohorts. Ciba Foundation Symposium, 194, 115–123.

Brown, C. S., Kent, T. A., Bryant, S. G., Gevedon, R. M., Campbell, J. L., Felthous, A. R., Barratt, E. S.,& Rose, R.M. (1989). Blood platelet uptake of serotonin in episodic aggression. Psychiatry Research, 27,5–12.

Brown, G. L., Ebert, M. H., Goyer, P. F., Jimerson, D. C., Klein, W. J., Bunney, W. E., & Goodwin, F. K.(1982). Aggression suicide, and serotonin: Relationships to CSF amine metabolites. American Journalof Psychiatry, 139, 741–746.

Cherek, D. R., Moeller, F. G., Khan-Dawood, F., Swann, A., & Lane, S. D. (1999). Prolactin response tobuspirone was reduced in violent compared to nonviolent parolees. Psychopharmacology, 142, 144–148.

Coccaro, E. F., Kavoussi, R. J., Lesser, J. C. (1992). Self- and other-directed human aggression: The roleof the central serotonergic system. International Clinical Psychopharmacology, 6(Suppl. 6), 70–83.

Coccaro, E. F., Kavoussi, R. J., Sheline, Y. I., Lish, J. D., & Csernansky, J. G. (1996). Impulsiveaggression in personality disorders correlates with tritiated paroxetine binding in the platelet. Archives ofGeneral Psychiatry, 53, 531–536.

Coccaro, E. F., Kavoussi, R. J., Trestman, R. L., Gabriel, S. M., Cooper, T. B., & Siever, L. J. (1997).Serotonin function in human subjects: Intercorrelations among central 5-HT indices and aggressive-ness. Psychiatry Research, 73, 1–14.

Courtet, P., Baud, P., Abbar, M., Boulenger, J. P., Castelnau, D., Mouthon, D., Malafosse, A., & Buresi,C. (2001). Association between violent suicidal behavior and the low activity allele of the serotonintransporter gene. Molecular Psychiatry, 6, 338–341.

Dolan, M., Anderson, I. M., & Deakin, J. F. (2001). Relationship between 5-HT function and impulsivityand aggression in male offenders with personality disorders. British Journal of Psychiatry, 178, 352–359.

Eysenck, S. B. G., Daum, I., Schugens, M. M., & Diehl, J. M. (1990). A cross cultural study ofimpulsiveness, venturesomeness and empathy: Germany and England. Zeitschrift fur differentielle unddiagnostische Psychologie, 11, 209–213.

Filley, C. M., Price, B. H., Nell, V., Antoinette, T., Morgan, A. S., Bresnahan, J. F., Pincus, J. H.,Gelbort, M. M., Weissberg, M., & Kelly, J. P. (2001). Toward an understanding of violence:Neurobehavioral aspects of unwarranted physical aggression: Aspen Neurobehavioral Conferenceconsensus statement. Neuropsychiatry, Neuropsychology and Behavioural Neurology, 14, 1–14.

Gobbi, G., Murphy, D. L., Lesch, K. P., & Blier, P. (2001). Modifications of the serotonergic system inmice lacking serotonin transporters: An in vivo electrophysiological study. The Journal of Pharmacologyand Experimental Therapeutics, 296, 987–995.



Gould, E. (1999). Serotonin hippocampal neurogenesis. Neuropsychopharmacology, 21, 46S–51S.Hallikainen, T., Saito, T., Lachman, H. M., Volavka, J., Pohjalainen, T., Ryynanen, O. P., Kauhanen, J.,

Syvalahti, E., Hietala, J., & Tiihonen, J. (1999). Association between low activity serotonin transporterpromoter genotype and early onset alcoholism with habitual impulsive violent behavior. MolecularPsychiatry, 4, 385–388.

Hansson, S. R., Mezey, E., & Hoffman, B. J. (1999). Serotonin transporter messenger RNA inneural crest-derived structures and sensory pathways of the developing rat embryo. Neuroscience, 89,243–265.

Heils, A., Teufel, A., Petri, S., Stober, G., Riederer, P., Bengel, D., & Lesch, K. P. (1996). Allelicvariation of human serotonin transporter gene expression. Journal of Neurochemistry, 66, 2621–2624.

Hiller, W., Zaudig, M., & Mombour, W. (1990). Development of diagnostic checklists for use in routineclinical care. Archives of General Psychiatry, 47, 782–784.

Hwu, H. G., & Chen, C. H. (2000). Association of 5HT2A receptor gene polymorphism and alcoholabuse with behavior problems. American Journal of Medical Genetics, 96, 797–800.

Kotler, M., Barak, P., Cohen, H., Averbuch, I. E., Grinshpoon, A., Gritsenko, I., Nemanov, L., &Ebstein, R. P. (1999). Homicidal behavior in schizophrenia associated with a genetic polymorphismdetermining low catechol-O-methyltransferase (COMT) activity. American Journal of Medical Genetics,88, 628–633.

Kruesi, M. J., Rapoport, J. L., Hamburger, S., Hibbs, E., Potter, W. Z., Lenane, M., & Brown, G. L.(1990). Cerebrospinal fluid monoamine metabolites, aggression, and impulsivity in disruptive behaviordisorders of children and adolescents. Archives of General Psychiatry, 47, 419–426.

Lappalainen, J., Long, J. C., Eggert, M., Ozaki, N., Robin, R. W., Brown, G. L., Naukkarinen, H.,Virkkunen, M., Linnoila, M., & Goldman, D. (1998). Linkage of antisocial alcoholism to the serotonin5-HT1B receptor gene in 2 populations. Archives of General Psychiatry, 55, 989–994.

Lesch, K. P., Bengel, D., Heils, A., Sabol, S. Z., Greenberg, B. D., Petri, S., Benjamin, J., Muller, C. R.,Hamer, D. H., & Murphy, D. L. (1996). Association of anxiety-related traits with a polymorphism inthe serotonin transporter gene regulatory region. Science, 274, 1527–1531.

Lesch, K. P., & Merschdorf, U. (2000). Impulsivity, aggression, and serotonin: A molecular psychobio-logical perspective. Behavioural Sciences and the Law, 18, 581–604.

Levitan, R. D., Kaplan, A. S., Masellis, M., Basile, V. S., Walker, M. L., Lipson, N., Siegel, G. I.,Woodside, D. B., Macciardi, F. M., Kennedy, S. H., & Kennedy, J. L. (2001). Polymorphism of theserotonin 5-HT1B receptor gene (HTR1B) associated with minimum lifetime body mass index inwomen with bulimia nervosa. Biological Psychiatry, 50, 640–643.

Lidberg, L., Tuck, J. R., Asberg, M., Scalia-Tomba, G. P., & Bertilsson, L. (1985). Homicide, suicideand CSF 5-HIAA. Acta Psychiatrica Scandinavica, 71, 230–236.

Linnoila, M., Virkkunen, M., Scheinin, M., Nuutila, A., Rimon, R., & Goodwin, F. K. (1983). Lowcerebrospinal fluid 5-hydroxyindolacetic acid concentration differentiates impulsive from nonimpulsiveviolent behavior. Life Sciences, 33, 2609–2614.

Manor, I., Eisenberg, J., Tyano, S., Sever, Y., Cohen, H., Ebstein, R. P., & Kotler, M. (2001). Family-based association study of the serotonin transporter promoter region polymorphism (5-HTTLPR) inattention deficit hyperactivity disorder. American Journal of Medical Genetics, 105, 91–95.

Miles, D. R., & Carey, G. (1997). Genetic and environmental architecture of human aggression. Journalof Personality and Social Psychology, 72, 207–217.

Nakamura, T., Matsushita, S., Nishiguchi, N., Kimura, M., Yoshino, A., & Higuchi, S. (1999).Association of a polymorphism of the 5HT2A receptor gene promoter region with alcohol dependence.Molecular Psychiatry, 4, 85–88.

New, A. S., Gelernter, J., Goodman, M., Mitropoulou, V., Koenigsberg, H., Silverman, J., & Siever, L. J.(2001). Suicide, impulsive aggression, and HTR1B genotype. Biological Psychiatry, 50, 62–65.

O’Keane, V., Moloney, E., O’Neill, H., O’Connor, A., Smith, C., & Dinan, T. G. (1992). Bluntedprolactin responses to d-fenfluramine in sociopathy: Evidence for subsensitivity of central serotonergicfunction. British Journal of Psychiatry, 160, 643–646.

Preuss, U. W., Koller, G., Soyka, M., & Bondy, B. (2001). Association between suicide attempts and 5-HTTLPR-S-allele in alcohol-dependent and control subjects: Further evidence from a Germanalcohol-dependent inpatient sample. Biological Psychiatry, 50, 636–639.

Raap, D. K., & van de Kar, L. D. (1999). Selective serotonin reuptake inhibitors and neuroendocrinefunction. Life Sciences, 65, 1217–1235.

Reist, C., Mazzanti, C., Vu, R., Tran, D., & Goldman, D. (2001). Serotonin transporter promoterpolymorphism is associated with attenuated prolactin response to fenfluramine. American Journal ofMedical Genetics, 105, 363–368.

Retz, W., Thome, J., Blocher, D., Baader, M., & Rosler, M. (2002). Association of attention deficithyperactivity disorder-related psychopathology and personality traits with the serotonin transporterpromoter region polymorphism. Neuroscience Letters, 319, 133–136.

424 W. Retz et al.


Retz-Junginger, P., Retz, W., Blocher, D., Stieglitz, R. D., Georg, T., Supprian, T., Wender, P. H., &Rosler, M. (2003). [Diagnostic validity and reliability of the WURS-k for retrospective diagnosis ofADHD]. Nervenarzt, 74, 987–993.

Retz-Junginger, P., Retz, W., Blocher, D., Weijers, H. G., Trott, G. E., Wender, P. H., & Rosler, M.(2002). [The German short-form of the Wender Utah Rating Scale (WURS-k) for the retrospectiveassessment of the hyperkinetic syndrome in adults]. Nervenarzt, 73, 830–838.

Sander, T., Harms, H., Dufeu, P., Kuhn, S., Hoehe, M., Lesch, K. P., Rommelspacher, H., & Schmidt,L. G. (1998). Serotonin transporter gene variants in alcohol-dependent subjects with dissocialpersonality disorder. Biological Psychiatry, 43, 908–912.

Schalling, D., Asberg, M., Edman, G., & Oreland, L. (1987). Markers for vulnerability to psychopathol-ogy: Temperament traits associated with platelet MAO activity. Acta Psychiatrica Scandinavica, 76,172–182.

Seeger, G., Schloss, P., & Schmidt, M. H. (2001). Functional polymorphism within the promoter of theserotonin transporter gene is associated with severe hyperkinetic disorders. Molecular Psychiatry, 6,235–238.

Virkkunen, M., Rawlings, R., Tokola, R., Poland, R. E., Guidotti, A., Nemeroff, C., Bissette, G.,Kalogeras, K., Karonen, S. L., & Linnoila, M. (1994). CSF biochemistries, glucose metabolism, anddiurnal activity rhythms in alcoholic, violent offenders, fire setters, and healthy volunteers. Archives ofGeneral Psychiatry, 51, 20–27.

Vitiello, B., & Stoff, D. M. (1997). Subtypes of aggression and their relevance to child psychiatry. Journalof the American Academy of Child and Adolescent Psychiatry, 36, 307–315.

Volavka, J. (1999). The neurobiology of violence: An update. Journal of Neuropsychiatry and ClinicalNeurosciences, 11, 307–314.

Wender, P. H. (1995). Attention deficit hyperactivity disorder in adults. New York: Oxford University Press.Zalsman, G., Frisch, A., Bromberg, M., Gelernter, J., Michaelovsky, E., Campino, A., Erlich, Z., Tyano,

S., Apter, A., & Weizman, A. (2001). Family-based association study of serotonin transporter promoterin suicidal adolescents: No association with suicidality but possible role in violence traits. AmericanJournal of Medical Genetics, 105, 239–245.



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Association of serotonin transporter promoter gene polymorphism with violence: relation with personality disorders, impulsivity, and childhood ADHD psychopathology