American Journal of Medical Genetics (Neuropsychiatric Genetics) 81:13–17 (1998)

Tryptophan Hydroxylase Genotype Is Associated

With Impulsive-Aggression Measures:
A Preliminary Study
Antonia S. New,1,2* Joel Gelernter,3,4 Yoram Yovell,1,2 Robert L. Trestman,1,2 David A. Nielsen,5
Jeremy Silverman,1,2 Vivian Mitropoulou,1,2 and Larry J. Siever1,2
1
Psychiatry Service-116A, Bronx Veterans Administration Medical Center, Bronx, New York
2
Department of Psychiatry, Mount Sinai School of Medicine, New York, New York
3
Psychiatry Service-116A, West Haven VA Medical Center, West Haven, Connecticut
4
Division of Molecular Psychiatry, Department of Psychiatry, Yale University School of Medicine,
New Haven, Connecticut
5
Laboratory of Neurogenetics, NIAAA, National Institutes of Health, Rockville, Maryland

To assess the relationship between two phe-
notypes in an extremely well-characterized
population of personality disorder patients–
impulsive aggression and prolactin re-
sponse to fenfluramine–and tryptophan hy-
droxylase (TPH) genotype, TPH genotype
(at an intronic polymorphic site) and pro-
lactin response to fenfluramine were as-
sessed in 40 Caucasian patients with per-
sonality disorder. Impulsive aggression was
assessed by using the Buss-Durkee Hostility
Inventory (BDHI). Twenty-one male pa-
tients with the ‘‘LL’’ genotype had higher
BDHI scores than men with the ‘‘UL’’ or the
‘‘UU’’ genotype. No relationship between ge-
notype and prolactin response to fenflur-
amine was found. It was concluded that im-
pulsive-aggressive behavior in male person-
ality disorder patients may be associated
with the TPH genotype. Am. J. Med. Genet.
(Neuropsychiatr. Genet.) 81:13–17, 1998.
© 1998 Wiley-Liss, Inc.
KEY WORDS: serotonin; genetics; personal-
ity disorders; polymorphism
INTRODUCTION
Impulsive-aggressive behavior presents a critical
challenge in the treatment of patients with personality
disorders, because it accounts for a substantial portion
Contract grant sponsor: NIMH; Contract grant numbers: RO1-
MH42827, K02-MH01387; Contract grant sponsor: NIH; Con-
tract grant number: 5 M01-RR00071.
*Correspondence to: Antonia S. New, M.D., Psychiatry Service-
116A, Bronx VA Medical Center, 130 West Kingsbridge Road,
Bronx, NY 10468.
Received 4 April 1997; Revised 13 June 1997
© 1998 Wiley-Liss, Inc.
of the morbidity and mortality associated with these
disorders, as manifested by self-injurious behavior, do-
mestic violence, assault, substance abuse, destruction
of property, and suicide. In particular, in patients with
borderline, antisocial, and histrionic personality disor-
ders, a high rate of repeated self-mutilation and epi-
sodic dyscontrol have been reported (Virkkunen, 1976;
Pattison and Kahan, 1983). This spectrum of behaviors
often leads to difficulty in maintaining job stability,
and the eruption of overt physical aggression can dis-
rupt family relationships. This study assesses the re-
lationship between impulsive aggression and genotype
at the tryptophan hydroxylase (TPH) locus (by using an
intronic polymorphism; Nielsen et al., 1992) in a well-
characterized clinical sample of patients with person-
ality disorders.
Evidence suggests that impulsive aggression is both
partially heritable and associated with abnormalities
in serotonergic functioning. Both twin (Coccaro et al.,
1993) and adoption (Bohman et al., 1984) studies sug-
gest a partially heritable basis for impulsive aggres-
sion. Studies of personality disorders show that the
trait of impulsive aggression, not the borderline diag-
nosis, is significantly heritable (Alnaes and Torgersen,
1989; Torgersen, 1992; Coccaro et al., 1993).
The selection of genes involved in serotonin function-
ing as candidate genes for influencing these behaviors
comes from the observation that decreased serotoner-
gic activity has been associated with impulsive aggres-
sion. Decreased serotonergic function has also been as-
sociated with irritable or impulsive aggression in per-
sonality disorder patients as well as in depressed
patients, normal volunteers, and violent alcoholic of-
fenders, as demonstrated by a range of indices from
cerebrospinal fluid (CSF) 5-hydroxyindolacetic acid (5-
HIAA; Linnoila et al., 1989, 1994; Virkkunen et al.,
1994) to challenge with serotonergic-enhancing agents
(Coccaro et al., 1989, 1996; O’Keane et al., 1992; Siever
and Trestman, 1993). The relationship between re-
duced serotonergic function and impulsive aggression,
14 New et al.
in fact, is one of the most robust and replicable findings
in biologic psychiatry.
In light of the apparently heritable component of im-
pulsive aggression and the association of attenuation
in serotonin functioning with this behavior, it is logical
to investigate the possibility that genetic differences in
determinants of serotonergic function, such as synthe-
sis, metabolism, and receptor sensitivity, may contrib-
ute to different susceptibilities to impulsive aggression.
Indeed, earlier studies demonstrated 1) an association
between a polymorphism in the TPH gene and suicide-
related behaviors in violent offenders (Nielsen et al.,
1994) and 2) an association between allelic variation in
the serotonin transporter gene and variations in anxi-
ety-related personality traits (Lesch et al., 1996). These
studies suggest that genetic differences in the seroto-
nin system may be associated with behavioral traits
related to impulsive aggression.
Polymorphisms in genes coding for gene products in-
volved in serotonin synthesis, reuptake, metabolism,
and receptors have been identified in nonhuman pri-
mates (Raleigh et al., 1994) and in human subjects,
including the TPH gene (Nielsen et al., 1994), the se-
rotonin transporter (SLC6A4) gene (Gelernter and
Freimer, 1994; Lesch et al., 1994, 1996), the 5-HT2C
receptor gene (Lappalainen et al., 1995), and the
5-HT2A receptor gene (Warren et al., 1993).
TPH is the first enzyme involved in the synthesis of
serotonin. A biallelic polymorphism in intron 7 of the
gene on chromosome 11 coding for TPH has been iden-
tified, and the two alleles have been designated ‘‘L’’ and
‘‘U’’ (Nielsen et al., 1992), with frequencies of 0.40 and
0.60, respectively, in unrelated Caucasians. In a Finn-
ish cohort of violent alcoholic offenders, the L TPH al-
lele was associated with reduced CSF 5-HIAA concen-
trations and a history of suicide attempts (Nielsen et
al., 1994, 1995). Although a subsequent report found no
association between suicidality and a TPH polymor-
phism in a sample of depressed patients (Abbar et al.,
1995), this study assessed a different TPH polymor-
phism from the Finnish study (Nielsen et al., 1994),
and whether the two polymorphisms are in linkage dis-
equilibrium is not known. Furthermore, there is also
preliminary evidence of an association between the L
allele and aggressive behavior in an analogous poly-
morphism in the TPH gene in primates (Raleigh, per-
sonal communication). It should be noted, however,
that the functional significance of this polymorphism
has yet to be established. Because this is an intronic
polymorphism, the two alleles probably do not code for
different gene products. However, the association with
clinical symptoms raises the possibility of linkage dis-
equilibrium or a change in a regulatory region close to
the TPH gene.
In light of the observation of serotonergic dysfunc-
tion in patients with impulsive aggression and the ap-
parent heritability of impulsive-aggressive behavior,
we assessed the relationship between impulsive ag-
gression and TPH genotype in our clinical sample of
patients with personality disorders. Furthermore, we
conducted an exploratory analysis of the relationship
between a functional measure of central serotonergic
activity, the prolactin response to fenfluramine (which
is dependent, at least in part, on presynaptic serotonin
synthesis), and TPH genotype.
MATERIALS AND METHODS
Subjects
Subjects consisted of 40 Caucasian personality dis-
order patients (21 males, 19 females). The subjects
were selected from the Bronx Veterans Administration
Medical Center (VAMC) outpatient clinic and the
Mount Sinai Medical Center outpatient clinic or from
referrals from outside mental health professionals. All
subjects participated in the project after informed con-
sent, as approved by the internal review boards of the
Bronx VAMC and the Mount Sinai Medical Center. All
subjects received a comprehensive medical evaluation,
including an extensive medical history, physical exami-
nation, and laboratory evaluation. Patients with evi-
dence of a serious systemic medical illness that might
influence central nervous system (CNS) function, such
as diabetes mellitus, autoimmune illness, HIV infec-
tion, persistent resting hypertension, or cardiac disor-
der, were excluded. In addition, patients with neuro-
logical impairment, such as those with a history of
stroke, seizures, or severe head trauma (with loss of
consciousness), were excluded, because these neuro-
logical impairments may influence the manifestations
of aggressive behavior. The subset of patients who un-
derwent fenfluramine challenge had additional restric-
tions: patients with thyroid or other endocrine disor-
ders or with a body weight more than 20% above ideal
were also excluded in order to eliminate the variance in
prolactin response to fenfluramine caused by endocrine
dysfunction or obesity. Women underwent fenflur-
amine challenge only in the first 10 days of their men-
strual cycle.
Patients were free of alcohol or drugs of abuse in the
2 weeks prior to clinical assessment, because acute in-
toxication may influence impulsive-aggressive symp-
toms. Patients with a past history of major alcohol
abuse and dependence were excluded, because they
may have had significant alcohol-related CNS damage.
Subjects with a history of IV drug abuse or persistent
cocaine use were excluded, because these behaviors
may be associated with CNS damage. No patient met
criteria for substance dependence for at least 6 months
prior to study, because withdrawal might influence ag-
gressive symptomatology.
The subjects all met DSM-IV criteria for one or more
personality disorders and had a range of impulsive-
aggressive symptomatology. Patients were excluded if
they met DSM-IV criteria for schizophrenia or any
schizophrenia-related psychotic disorders or for bipolar
(Type I) affective disorder, because these diagnoses
may influence the expression of impulsive-aggressive
behavior.
Subjects may have met criteria for major depressive
disorder in the past and may have had intermittent
depressive symptomatology, which is common in
the personality disordered population. We did not
include patients with a current, longstanding, major
depression, because we would not be able to discern
the underlying personality disorder symptoms, al-

though some patients had transient depressive symp-
toms.
Because allele frequency at this locus differs across
population groups (Gelernter et al., 1997), we report
data here only from Caucasian patients. Because males
and females may have different phenotypic expressions
of aggression and may have a different relationship
between the serotonergic system and aggression, the
results for males and females are reported separately.
Informed consents (with an independent clinician as-
sessing capacity to consent) were obtained, as approved
by the internal review boards of the Bronx VAMC and
the Mount Sinai Medical Center.
Diagnostic Assessment
All subjects were interviewed by one or two experi-
enced raters using the Schedule for Affective Disorder
in Schizophrenia-Lifetime version (SADS-L; k 4 0.81)
for axis I disorders and the Structured Interview for
the Diagnosis of DSM-III-R personality disorders
(SIDP-R; k 4 0.81) for borderline personality disorder.
History of suicide attempts was derived from the
SADS-L (Endicott and Spitzer, 1978).
Assessment of Impulsivity
Impulsivity and aggression were rated by both self-
report measures and by observer ratings. The report
measures used included the Buss-Durkee Hostility In-
ventory (BDHI; Buss and Durkee, 1957) and the Bar-
ratt Impulsivity Scale (BIS; Barratt, 1965). These mea-
sures have been validated extensively in the psycho-
metric literature.
Isolation of DNA and Genotyping
Genotypes were obtained by using the polymerase
chain reaction (PCR)-RFLP method. DNA was ex-
tracted from blood by using a modification of the
method of Lahiri and Nurnberger (1991). Genomic
DNA (50 ng) was amplified with PCR by using the PCR
primers of Nielsen et al. (1992). After amplification,
PCR products were digested with BfaI (NE Biolabs,
Beverly, MA) and were then electrophoresed. The un-
cut amplicon is 918 base pairs (bp) long. After diges-
tion, the U allele has 860- and 58-bp fragments, and
the L allele has 615-, 245-, and 58-bp fragments.
Fenfluramine Challenge Test
Subjects were maintained free of medication for 2
weeks prior to the protocol. Fenfluramine (60 mg) or
placebo was administered orally at 10 A.M., and blood
samples for prolactin were drawn 15 and 5 minutes
before the infusion and hourly after the challenge for 5
hours. d-Prolactin was defined as the maximal prolac-
tin concentration between hours 3 and 5 minus the
baseline prolactin concentration. The prolactin concen-
trations were determined in plasma by radioimmuno-
assay (intraassay variability < 7% in 12 iterations; in-
terassay variability < 9% in 30 iterations).
Statistical Analyses
The male and female patients were analyzed sepa-
rately. Male Caucasian patients with the ‘‘LL’’ geno-
TPH and Aggression 15
type were compared with those with either the ‘‘UL’’ or
the ‘‘UU’’ genotypes by using a Student’s t-test [be-
cause the UU genotype was relatively rare (n 4 2 for
males), we combined the UL and the UU groups]. A
comparable analysis was performed for females. The
Pearson correlation coefficient was used for correla-
tional analyses between prolactin response to fenflur-
amine and genotype and between history of suicide at-
tempt and total number of impulsive borderline per-
sonality traits and the LL genotype. All P values
reported are two-tailed.
RESULTS
In the 21 male Caucasian patients, the LL genotype
group had significantly higher scores on the BDHI total
score (45.3 ± 9.8) compared with Caucasian males with
the UL or UU genotypes (32.9 ± 13.5; t 4 2.38; df 4 19;
P < 0.03; see Fig. 1) as well as significantly higher
scores on the BDHI irritability plus assaultiveness sub-
scale (Table 1). The range of BDHI total irritability
plus assaultiveness scores was broad, allowing com-
parisons between highly impulsive and unimpulsive in-
dividuals. No significant association was found be-
tween the LL genotype and a history of suicide attempt
or impulsive borderline personality disorder traits in
this sample. Like in the previous studies, the BDHI
assault plus irritability subscales correlated negatively
with the prolactin response to fenfluramine (r 4 −0.70;
n 4 16; P < 0.01) in the 16 male patients who had the
fenfluramine challenge. Patients with the LL genotype
demonstrated a nonsignificant (ns) lower prolactin re-
sponse to fenfluramine compared with the UL or UU
genotypes (9.4 ± 5.0 vs. 13.5 ± 10.3; n 4 16; t 4 1.05;
df 4 14; P 4 ns). Females with the LL genotype did not
demonstrate higher BDHI scores or a blunted prolactin
response to fenfluramine.
DISCUSSION
A significant association was found between irritable
or impulsive aggression, as measured on the BDHI,
and the TPH LL genotype in males, and no such asso-
ciation was found in the female sample. The restriction
of association to the males is consistent with evidence
suggesting sex differences in the expression of aggres-
Fig. 1. Prolactin response to fenfluramine in Caucasian male patients
by allele type.
16 New et al.
TABLE I. Allele Type and Clinical Characteristics in
Caucasian Males (Mean ± SD)
LL UL UU UL + UU
N 10 9 2 11
BDHI
Total score* 45.3 ± 9.8 30.3 ± 13.6 44.5 ± 4.2 32.9 ± 13.5
Range 20–63 11–61 16–48 11–61
Irritability + assault
Score* 14.5 ± 3.2 8.8 ± 6.7 14.5 ± 2.1 9.9 ± 6.1
Range 3–21 1–19 6–16 1–19
Suicide history 3 2 0 2
*LL > UL + UU; P < .05. L allele frequency 4 0.52; U allele frequency 4
48. BDHI, Buss-Durkee Hostility Inventory.
sion as well as in behavioral correlates of serotonergic
function in men and women (New et al., 1997). Previ-
ous studies in our group have suggested that reduced
serotonergic activity is associated most closely with im-
pulsive aggression in males, so that it was hypoth-
esized that the LL genotype would display a higher
degree of impulsive aggression than the two other
genotypes, UL and UU (the L allele was reported pre-
viously to be associated with decreased CSF 5-HIAA,
as discussed above). Exploratory analyses were also
performed regarding the relationship of impulsive ag-
gression and the LL genotype in females. Although the
sample size was modest, this is the first study to evalu-
ate TPH genotype in a well-characterized clinical
sample of personality disorder patients.
These results complement those of Nielsen and col-
leagues (1995). Their sample consisted of Finnish
criminal offenders with uniform histories of aggres-
sion, although there may have been some variability in
impulsivity. In our sample of patients with personality
disorders, there was considerable variation in impul-
sive aggression, in that the population was not re-
stricted specifically to patients with those personality
disorders associated with aggressive behaviors, such as
borderline or antisocial personality disorders. The
number of suicide attempts in this pilot study was also
small. Thus, the greater variance with regard to irri-
table aggression and the reduced variance in suicide
history in this sample compared with the Nielsen
sample may account for the difference in correlations
observed between the two groups.
A significant correlation was found between the
BDHI scores and the d-prolactin response to fenflur-
amine, as in previous studies (Coccaro et al., 1989). The
association between the d-prolactin response to fenflu-
ramine and the LL genotype was not significant in this
small sample, although the mean d-prolactin was lower
in the LL group, raising the possibility that this differ-
ence might be significant in a larger sample.
With regard to all of the association studies of this
general design, numerous caveats apply (Gelernter and
Freimer, 1994). Although there have now been several
positive studies relating TPH genotype to aspects of
behavior (specifically, suicidality; Nielsen et al., 1994;
Mann et al., 1997), it is difficult to view all of these
results, considered along with ours, as wholly consis-
tent, although the differences observed may reflect the
different composition by diagnosis of the various stud-
ies. If the latter explanation is the correct one, then
these results can be taken as encouraging, but they
clearly require either replication in larger samples or
demonstration of a mutation in the gene that clearly
affects protein structure or regulation before they can
be accepted.
Furthermore, multiple genes are likely to contribute
to complex traits, such as irritable aggression, and the
association of specific genes with a trait may be quite
modest and may vary between samples. Genetic vul-
nerability is likely to be compounded by environmental
factors in the expression of impulsive aggression,
which may further contribute to a modest gene trait
relationship. Finally, the different alleles of the TPH
gene are common in the population and are unlikely to
be associated with a specific illness. Rather, it is more
likely that individuals with alleles conferring greater
vulnerability to aggression in multiple serotonin-
related genes will manifest clinically significant impul-
sive aggression. This approach suggests that it will be
important to assess the genotype of numerous seroto-
nin-related genes in patients with impulsive-
aggressive behavior in order to look for the interacting
effects of having more than one gene associated with
risk for impulsive aggression.
ACKNOWLEDGMENTS
Ann Marie Wantroba provided excellent technical
assistance. This research was supported by NIMH
grants RO1-MH42827 and K02-MH01387, by a VA De-
partment Merit Award to Drs. Larry J Siever and Joel
Gelernter, and by NIH grant 5 M01-RR00071 to the
Mount Sinai General Clinical Research Center. This
paper was presented at the Annual Meeting of Biologi-
cal Psychiatry in 1996.
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