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Genes for personality traits : implications for
psychopathology
TR E N D S A N D
PERSPECTIVES
International Journal of Neuropsychopharmacology (1998), 1, 153–168. Copyright # 1998 CINP
Jonathan Benjamin1, Richard P. Ebstein2 and Klaus-Peter Lesch3
" Laboratory of Clinical Science, National Institute of Mental Health, Bethesda, Md, USA, Division of Psychiatry, Soroka
Medical Center and Ben Gurion University of the Negev, Beer-sheba, Israel
# Research Laboratory, S. Herzog Memorial Hospital, Jerusalem, Israel
$ Department of Psychiatry, University of Wuerzburg, Germany
Abstract
Although 30–60 % of the variance in many personality traits is inherited, until recently, little was known about
the genes responsible. Preliminary studies of family history in bipolar disorder and of X-linkage of personality
traits in colour-blindness suggested a ‘ quantitative trait locus ’ (QTL) approach to the genetics of normal
personality. In methodically similar but independent studies of 124 Israeli and 315 American normal
volunteers, an association was found between the dopamine D4 receptor gene (D4DR) and the personality trait
of novelty-seeking. In the Israeli sample there was preliminary evidence for an interaction between the D4DR
gene and the serotonin 2C receptor gene (5-HT-2C), with a marked effect on the trait of reward dependence.
In addition to receptors, monoamine uptake mechanisms, such as the serotonin transporter (5-HTT), are
candidate genes for personality traits. 5-HTT gene transcription is modulated by a frequent polymorphism in
its promoter region, with resulting effects on 5-HTT expression and 5-HT uptake. In an extended American
sample totalling 505 subjects, the 5-HTT polymorphism was associated with anxiety- and depression-related
personality traits. The allelic variation in functional expression of the 5-HTT may also be a susceptibility factor
for disorders of the affective spectrum. Further investigation of genes for personality traits may provide
additional links between normal personality and psychiatric illness.
Received 19 January 1998 ; Reviewed 22 March 1998 ; Revised 21 May 1998 ; Accepted 24 June 1998
Key words : Anxiety, depression, dopamine, genetics, personality, serotonin.
Introduction
Human personality and behaviour are partly inherited.
Twin and family studies have demonstrated that certain
behavioural disorders, such as reading disability and male
alcoholism, may have larger genetic components than
traditional polygenic medical disorders such as hypertension and ischaemic heart disease (Plomin et al., 1994).
Normal personality traits, as measured by dimensional
scales of personality assessment, present the same pattern,
with inheritance typically accounting for between 30
and 60 % of the observed variance. One example is
provided by the striking similarity of identical twins
adopted out and reared apart (the Minnesota Study),
some of whom had not known each other prior to the
study (Bouchard et al., 1990). On measures of interests,
Address for correspondence : Dr J. Benjamin, Psychiatry Department,
Soroka Medical Center, PO Box 151, Beer-sheba 84101, Israel.
Tel. and Fax : j 972-7-6400783
E-mail : yonatan!bgumail.bgu.ac.il
skills and personality traits, these twins had correlations
between 34 % and 78 %. By contrast, fraternal twins
studied by the same investigators had correlations
between 7 % and 39 % (Tellegen et al., 1988). Virtually all
work in this area supports the idea that there is a
substantial heritable component to personality
(Henderson, 1982 ; Loehlin et al., 1988 ; Plomin, 1990).
Despite the psychometric evidence that personality is
influenced by genetic factors, until recently very little was
known of the number or nature of the genes responsible.
One approach to identifying such genes is linkage
analysis, which is based on the principle that if a gene
influences a trait, then family members who share a
chromosomal region harbouring that gene will be more
similar on that trait than relatives who have different
versions of that region. The advantages of linkage analysis
are that it scans large segments of DNA and does not
require prior knowledge of the mode of inheritance or
biochemical mechanism of the relevant genes. The
disadvantage is that it is relatively insensitive to genes
with small effect sizes.
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J. Benjamin et al.
A second approach for identifying genes that are
related to personality or other behavioural characteristics
is allelic association, which is based on the principle that if
a gene influences a trait, then individuals who share a
particular allelic variant of the gene should be more similar
to one another than are individuals with different alleles.
This approach is most powerful when candidate genes
that are ‘ biologically reasonable ’, and that have known
functional polymorphisms, are available. The main advantage of allelic association is that it is remarkably
sensitive to small effect sizes.
Until recently, there had been no published reports of
linkage and association analyses of normal personality
traits. In principle, however, such traits should be as
amenable to study as physical traits. Quantitative traits
(sometimes called ‘ dimensional traits’)" have been successfully analysed by this method in many non-human
species. The idea behind this approach is not to look for a
single gene with an ‘ all-or-nothing ’ effect, as in
Huntington’s chorea, but rather for a number of genes,
each with a small effect by itself but with large combined
effects. Genes with small effects may underlie a dimensional trait, like height or intelligence, and they may also
underlie the risk of developing an ‘ oligogenic ’ disease like
pyloric stenosis or perhaps schizophrenia (Benjamin et al.,
1996a). If major mental illnesses (and\or personality
traits) are due to single genes with large effects (i.e.
Mendelian), then it should not be too difficult to find
affected relatives in a high proportion of affected
probands, provided pedigrees are large enough. Alternatively, a low proportion of probands who have affected
relatives suggests an oligo- or polygenic effect ; it is
unusual for any relative other than an identical twin to
share exactly the same combination of genes needed to
influence (or even cause) the illness.
Frequency of positive family history in bipolar
patients
The Division of Psychiatry of Ben Gurion University of
the Negev serves practically all psychiatric patients in its
catchment area of 300 000, and its two affective disorder
clinics have a record of lithium-treated patients in the area.
The files of all bipolar I and schizoaffective patients
registered with the clinics in 1991 (n l 236) were
reviewed (Alexander et al., 1995). One hundred and
seventy-seven probands were personally interviewed
about their family histories, as were 50 of their relatives.
All the studies described in this paper were approved by
" If investigators hypothesize a number of genes influencing the trait,
with each gene exerting a small effect on its own, the chromosomal
regions thought to harbour such genes are sometimes called ‘ QTLs ’,
for ‘ quantitative trait loci ’.
the Helsinki Committees of the relevant medical
institutions.
Out of 177 interviewed patients, 103 (58 %) had
positive family histories. Out of the entire sample of 236
patients, 113 (48 %) had positive family histories. Since
the population prevalence of lithium-treated individuals
in Europe is about 1.3 per 1000 (Vestergaard et al., 1989),
and over one-third of the population of the Negev is
below the age of risk for affective illness, about 250
lithium-treated patients would be expected in a catchment
area of 300 000. The present sample of 236 seems to have
been fairly comprehensive. About half of the bipolar
patients, therefore, have no family history of a condition
with an undoubted (partly) genetic etiology. This was
also shown about 25 years previously (Winokur, 1973).
We interpreted this as circumstantial evidence that manicdepression is a non-Mendelian disorder.
The case for studying genes for normal personality
traits
The difficulties encountered in the search for single major
genes for mental illnesses like schizophrenia and manicdepression (Baron et al., 1990 ; Risch et al., 1996) need to
be considered in the light of this possibility, that each of
the genes involved contributes only a small part of the
variance. And indeed, the new ‘ small gene ’ approach
(Benjamin et al., 1996a) has begun to yield exciting
findings for the psychoses, for example, weak but
replicated linkages (that is, presumably valid linkages to
genes with small effects) to chromosome 18 in manicdepression (Berrettini et al., 1994 ; Stine et al., 1995) and to
chromosome 6 in schizophrenia (Moises et al., 1995 ;
Peltonen, 1995 ; Schwab et al., 1995 ; Straub et al., 1995 ;
Wang et al., 1995). A further complication is that it
appears increasingly likely that psychiatric diseases are
both polygenic and genetically heterogeneous (Belmaker
et al., 1994 ; Cloninger, 1994). If, as has been suggested,
the same psychiatric syndrome can result from differing
combinations of environmental effects and inherited
personality variants (Bleuler, 1952 ; Goodwin et al., 1990)
even in the same family (Cloninger, 1994), then these will
be difficult to detect with linkage and association studies,
which treat the syndrome as a single phenotype. Instead,
further progress may depend on the identification of
simpler underlying ‘ endophenotypes ’ (Gottesman, 1991).
A plausible analogy may be drawn from the case of
myocardial infarction, where it is cholesterol levels, blood
pressure and so on, not the infarct itself, that are inherited.
Normal personality traits, or extreme variants of these,
represent prima facie candidates for the role of ‘ endophenotypes ’ for mental illnesses, and there is some
evidence for a continuum between normal personality
Genes for personality traits
traits, personality disorders and psychiatric illness. The
normal personality trait of novelty-seeking (see below) is
high in ‘ cluster B ’ type personality disorders like antisocial
personality (Svrakic et al., 1993) and alcoholism (Mulder
et al., 1994), and the trait of reward dependence (see
below) is low in ‘ cluster A ’ type personality disorders,
like schizoid and schizotypal disorders (Svrakic et al.,
1993). Consequently, personality disorders may represent
extremes of normal personality traits. Mental illnesses, in
turn, may be extreme variants of personality disorders, for
example, schizoid and schizotypal personality disorders
and schizophrenia (Nigg et al., 1994). Basic personality
traits like novelty-seeking, harm avoidance and reward
dependence may, via a complicated nonlinear path that
leads in the first instance to personality disorders,
ultimately predispose to psychosis. One possible route
could be a maladaptive trait, or traits, which might
interact with other biologic and\or environmental risk
factors to produce manifest illness. In keeping with this
line of thinking, Kendler and colleagues have shown that,
in 707 pairs of female twins who completed two scales of
the Eysenck Personality Questionnaire and were assessed
for the presence of depression, about 70 % of the risk of
depression was inherited (Kendler et al., 1993a, b). Of this
heritability, 45 % was direct, while the other 55 % was via
the effect of the inherited personality trait ‘ neuroticism ’.
Therefore a series of linkage and association studies of
normal (adaptive) personality traits was initiated, with the
prediction that positive findings might ultimately elucidate the neurobiology of complex behavioural phenotypes and provide a bridge to the pathophysiology of
(maladaptive) personality disorders and serious mental
illnesses.
Linkage between colour-blindness and personality
traits
Because there is substantial evidence of linkage of manicdepressive illness to the colour-blindness locus on the X
chromosome (Baron et al., 1987 ; Souery et al., 1995), it
was reasoned that the locus might also play a role in
normal personality or variations of normal mood.
Benjamin et al. (1993) adapted the sib-pair method
(Suarez et al., 1982) to their QTL approach, and
hypothesized that a personality trait or traits would show
a significantly higher correlation between pairs of brothers
concordant for colour-blindness (both affected) than
between pairs of brothers discordant for colour-blindness
(only one affected). Colour vision was assessed with
Ishihara’s test. To evaluate personality, the Sixteen
Personality Factor Questionnaire (16PF) (Cattell et al.,
1970) was used. The 16PF questionnaire is based on a
factor-analytic model of personality and has been exten-
155
sively used in four decades of personality research (for
example, Loehlin, 1992). It is available in a validated
Hebrew version. Seventeen probands participated in
this pilot study. A single factor, Q2, correlated significantly between concordant, but not between discordant
brothers.
Although the sample was very small and the finding
necessarily preliminary, the study was important as a first
attempt to map a gene for a personality trait. In the
interim there have been reports of personality traits in
relation to the debrisoquine metabolism polymorphism
(LLerena et al., 1993) and of defence mechanisms in
relation to a dopamine D2 receptor polymorphism
(Comings et al., 1995). While intriguing, these three
studies have not yet been replicated.
Association studies of the dopamine D4 receptor
gene (D4DR)
There has been renewed interest in the genetics of
dopamine receptors, following the discovery of polymorphisms in the dopamine D3 (D3DR) (Rietschel et al.,
1993) and D4 receptor genes (D4DR) (Van Tol et al.,
1992). Cloninger (1987) had previously described a
biological approach to personality assessment, embodied
in the Tridimensional Personality Questionnaire (TPQ).
On the basis of animal and human studies and statistical
analyses, he suggested there were three underlying,
inherited dimensions of human temperament, one of
which, novelty-seeking, should be mediated by dopamine.
Exploratory behaviour in animals is mediated by dopamine
(Kalivas et al., 1988) and so are the effects of cocaine and
amphetamines in man (Ritz et al., 1993). Novelty-seeking
has been reported to be low in Parkinson’s disease
patients, who have dopaminergic deficiencies (Menza et
al., 1993).
D4DR seemed a good candidate gene for a behavioural
trait : it is expressed in limbic brain regions involved in
cognition and emotion (Meador-Woodruff et al., 1994) ; it
was reported to be elevated six-fold in post-mortem
brains of schizophrenics (Seeman et al., 1993) and it binds
the atypical antipsychotic agent clozapine 14 times more
tightly than does the D2 receptor (Van Tol et al., 1992
and references therein). It has recently been reported that
mice who have had the D4 receptor ‘ knocked out ’ behave
differently in an open field and after administration of
alcohol and cocaine (Rubinstein et al., 1997). The third
exon of D4DR contains a highly variable 48 bp
repeat sequence, and alleles with different numbers of
repeats differ in their ability to bind dopamine (Van Tol et
al., 1992) and inhibit adenylyl cyclase (Asghari et al.,
1995). Thus the polymorphism might have physiological
significance. Despite a lack of evidence for associations
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J. Benjamin et al.
between schizophrenia and D4DR polymorphisms
(Nanko et al., 1993 ; Sommer et al., 1993), a study of
personality, and in particular of novelty-seeking, and
D4DR in normal individuals seemed warranted.
Ebstein et al. (1996) analysed TPQ scores and D4DR
exon III alleles in 124 healthy Israeli volunteers ; subjects
were recruited from the staff of a psychiatric hospital, but
did not undergo formal psychiatric screening. As predicted, TPQ novelty-seeking was significantly associated
with the D4DR polymorphism (p l 0.013) ; individuals
with the longer, seven-repeat alleles had higher noveltyseeking scores. There was no association with other TPQ
trait scores (Table 1a). The results did not appear to
represent the false positive association known as
‘ population stratification ’.
Population stratification refers to chance associations
between an allele and a trait, owing to the fact that both
are associated with a particular ethnic group. For example,
if a particular HLA antigen is common in a certain ethnic
group, and so is low stature or high sociability, then a
study which includes members of that group and members
of other groups will find spurious ‘ genetic ’ associations
between the antigen and the trait in the study population
overall. This can be corrected for by ‘ transmission tests ’,
which look for the same association only in families in
which subjects have different alleles of the locus in
question ; individuals, or families whose members all share
only one of the alleles being studied, are excluded from
analysis.# Since members of families are more ethnically
similar than members of the population, gene-trait
associations within families are presumed to be due to
genetic transmission, not artefacts of ethnicity. We found
similar allele frequencies and similar allele-TPQ
associations in the various ethnic groups in this sample,
suggesting that the finding was not a case of population
stratification ; the absence of families in the study made it
impossible to exclude this possibility more conclusively.
Three hundred and fifteen individuals (mostly sib-pairs)
were available in an American sample (Benjamin et al.,
1996b), who had given blood samples and completed the
NEO Personality Inventory – Revised (NEO-PI-R) personality test (Costa et al., 1992, 1996 ; McCrae et al.,
1990) and the 16PF. The NEO is based on the five-factor
model of personality, a dominant model in current
psychological theories of personality assessment
(Digman, 1990). Some of these subjects were from an
ongoing X-linkage study of normal personality traits, and
others were from an X-linkage study of sexual orientation
(Hamer et al., 1993). Subjects were recruited from the
general public, and did not undergo formal psychiatric
screening. On a self-report screening questionnaire they
# Other corrections also exist.
were asked about individual and family mental problems
and substance abuse. Although the NEO-PI-R does not
include novelty-seeking as a specific factor, it contains
multiple items that are clearly related to questions from
the TPQ novelty seeking scale, e.g. ‘ I have sometimes
done things just for kicks or thrills ’, versus ‘ I often try
new things just for fun or thrillsh, and ‘ I think things
through before coming to a decisionh, versus ‘ I like to
think about things for a long time before I make a
decisionh. Recent studies of populations administered
both the NEO-PI-R and the TPQ have shown correlations
of about 70 % between novelty-seeking and NEO factors,
largely due to positive loading on NEO ‘ extraversion ’
and negative loading on NEO ‘ conscientiousness ’. It was
therefore predicted that these subjects would show a
positive association between long (see below) D4DR
exon III alleles and extraversion, a negative association
between long D4DR exon III alleles and conscientiousness, and a positive association between long
alleles and estimated novelty-seeking, calculated from
these data, using appropriately weighted equations derived from the studies using both questionnaires (McCrae
et al., 1990, available on request).
Of the 315 subjects there were 291 sibs from 131
families, 7 parents, and 17 unrelated individuals. Ninetyfive per cent were males and 92 % of the sample were
white. As in Ebstein et al. (1996), most of the alleles in this
sample included 4 or 7 repeats in the hypervariable exon
III. However, because there was a fair number of subjects
with 5-, 6- and 8-repeat alleles, and it was thought
desirable to use all available information, the length was
divided at the mid-point between 4 and 7, that is, 5–6 ;
alleles with 5 or fewer repeats were classified as ‘ short ’,
while those with 6 or more were classified as ‘ long ’.
(Additional analyses considering only 4- and 7-repeat
alleles did not change the results.) As in Ebstein et al.
(1996), short-short homozygotes were considered S ; the
presence of one or two long alleles resulted in a subject’s
classification as L. Table 1b shows ANOVA of the 5 major
NEO factors and estimated novelty-seeking, with presence or absence of a long allele (L) as the independent
variable. As predicted, ‘ extraversion ’ scores were significantly higher (p l 0.001) and ‘ conscientiousness ’ scores
were significantly lower (p l 0.03) in L subjects. Estimated
novelty-seeking was also significantly higher among L
subjects (p l 0.002).
To test for true genetic transmission, as opposed to
population stratification, all unrelated individuals and all
families which included individuals with only short or
only long alleles were excluded. This left 60 ‘ long-short ’
(L-S) pairs, who were subjected to a paired t test with
conservative corrections for non-independence of multiple sib-pairs. Table 2 shows that the same associations
Genes for personality traits
157
Table 1. Population associations between D4DR genotype and personality traits
Mean (..) Raw score
(a) TPQ factor
7 allele
absent
(n l 90)
7 allele
present
(n l 34)
F
∆D4DR
p value
Novelty seeking
Reward dependence
Harm avoidance
15.45 (0.5)
18.71 (0.4)
12.53 (0.6)
17.94 (1.0)
19.26 (0.7)
13.00 (1.0)
6.34
0.47
0.25
2.5
0.6
0.5
0.013
ns
ns
∆D4DR
p value
Mean (..) T score*
(b) NEO factor
Neuroticism
Extraversion
Openness
Agreeableness
Conscientiousness
TPQ novelty seeking
(estimated)
S group
(n l 217)
L group
(n l 98)
F
53.1 (9.1)
53.4 (9.7)
58.5 (9.7)
46.1 (9.5)
45.9 (10.3)
55.1 (7.9)
52.3 (9.2)
57.3 (10.3)
59.7 (11.1)
48.3 (9.9)
43.2 (10.7)
58.1 (7.0)
0.5
10.7
0.9
3.6
4.7
10.2
k0.8
3.9
1.2
2.2
k2.7
3.0
ns
0.001
ns
ns
0.03
0.002
* Transformed to a score with a population mean l 50, .. l 10.
Modified from (a) Ebstein et al. (1996a) and (b) Benjamin et al. (1996b).
Table 2. Within pedigrees associations between D4DR
genotype and personality traits. (n l 60 L-S pairs)
Factor
Extraversion
Conscientiousness
Novelty-seeking
(estimated)
∆D4DR*
6.8
k4.7
4.6
Paired t †
p value
2.9
2.3
2.8
0.008
0.03
0.01
* ∆D4DR l mean (L sib’s score – S sib’s score), in each
L-S pair.
† Conservatively corrected for nonindependence of sib-pairs
from the same family (from Benjamin et al. 1996b).
were found in this family analysis as in the whole study
population.
In addition to the strength of the statistical significance,
it is important to consider the effect size of the gene.
Figure 1 shows that D4DR was responsible for about 5 %
of the total variance, and affected the scores by about
10 %, or 0.4 standard deviations. The effect size in the
Israeli study was similar. This is considered a moderate
effect (Cohen, 1988). Novelty-seeking is about 40 %
heritable (Heath et al., 1994), so that D4DR accounts for
about an eighth of the genetic effects. Clearly, both other
genes and non-genetic influences affect novelty-seeking.
Figure 1. Distributions of estimated novelty-seeking scores.
The x axis shows the estimated TPQ-novelty-seeking scores
separated into 8 groups with the indicated median T scores.
The y axis shows the distribution, in percent, of subjects with
short D4DR exon III alleles (group S, n l 217, hatched bars),
and the distribution, in percent, of subjects with long D4DR
exon III alleles (group L, n l 98, solid bars).
To our knowledge these are the first replicated reports
of a gene for a personality trait. They are made more
convincing by the fact that the two studies used different
ethnic groups and different personality questionnaires,
158
J. Benjamin et al.
and yet both studies found essentially the same result.
However, two recent Scandinavian studies (Jonsson et al.,
1997 ; Malhotra et al., 1996), three American studies
(Gelernter et al., 1997 ; Pogue-Geile et al., 1998 ;
Vandenbergh et al., 1997), and a New Zealand study
(Sullivan et al., 1998), failed to replicate this finding. These
studies inevitably differed somewhat in their design and
subject populations ; in particular, Malhotra et al. recruited
alcoholic subjects and relatives, while Gelernter et al.
included subjects with substance abuse and normal
controls. There have also been two partial replications,
one by the present group (Ebstein et al., 1997d) and
another in Japan (Ono et al., 1997). In the first of these, the
association was in the same direction but was statistically
significant with only some of the significance tests
employed. In the second study, only the ‘ exploratoryexcitability ’ subscale of the novelty-seeking dimension
differed significantly by D4DR allele type. The original
reports, heuristic as they have proved, cannot therefore be
considered in any way definitive (Baron, 1998 ; Ebstein et
al., 1997a). In the interim, associations have been reported
between the long allele and the presence of attention
deficit hyperactivity disorder (LaHoste et al., 1997), heroin
abuse (Kotler et al., 1997 ; Li et al., 1997), and gambling
(Perez de Castro et al., 1997), all conditions with prima
facie resemblance to the impulsive aspect of noveltyseeking.
It has been suggested (Baron, 1998) that the problem of
non-replication of association studies could be
ameliorated by raising the threshold for significance to
correct for multiple-testing, as is customary in linkage
studies ; a linkage study with 300 markers that found
linkage at a particular locus would correct for 300 tests,
for example. However, in whole-genome linkage studies,
there is no a priori hypothesis concerning any given
marker, whereas in association studies there is usually
some hypothesis. The initial finding of an association
between D4DR and the novelty seeking-scale was
predicted, in part, by the personality theory underlying
the test employed (Cloninger, 1987). This is even more
the case with replication studies. Hopefully, additional
research among various ethnic and diagnostic groups will
elucidate the relationships between ethnicity, D4DR and
novelty-seeking.
Association study of the dopamine D3 receptor
gene (D3DR)
Like D4 receptors, D3 receptors are expressed in limbic
regions and bind antipsychotic drugs. A dopamine D3
receptor polymorphism in a coding region has been
described (Rietschel et al., 1993) but its physiological
significance is unknown. There have been controversial
reports of associations with homozygosity for the
polymorphism in schizophrenia (Crocq et al., 1992 ; Mant
et al., 1994), and one report of an association with bipolar
disorder (Parsian et al., 1995).
Genotypic D3DR data were available for 124 subjects
(Ebstein et al., 1997e). These were subjected to analyses of
TPQ factor scores. Table 3 shows that, in contrast to the
findings with the D4DR polymorphism, there were no
significant associations between various D3DR alleles and
the TPQ personality traits (although there was a weak
D4DRiD3DR interaction effect on reward dependence ;
p l 0.03, not corrected for multiple comparison
(Benjamin et al., 1998)).
Interaction between a 5-HT2C receptor gene
polymorphism and D4DR – effect on personality
It has already been pointed out that two or more genes,
each with small individual effects, may exert synergistic
effects when acting in concert. These so-called gene–gene
interactions may yet provide major breakthroughs in
behavioural genetics.
The 5-HT-2C receptor gene is widely expressed in the
brain, where it is involved in the regulation of various
responses, including the production and secretion of
ACTH, oxytocin and prolactin (Lappalainen et al., 1995).
The functional state of 5-HT-2C receptors in normal
controls and various patient groups has been studied in
vivo by administering m-CPP, 5-HT-2C agonist, and
measuring hormonal and psychological responses. In
alcoholism, panic disorder, seasonal affective disorder and
obsessive–compulsive disorder, m-CPP has been shown
to induce different hormonal and psychological responses
in patients and controls. A 2-allele polymorphism, a
cysteine to serine subsitution at amino acid 23, with a
frequency in the population of 0.13 was recently detected
(Lappalainen et al., 1995).
This polymorphism was typed in the 124 Israeli
subjects described above (Ebstein et al., 1997e). The traits
of reward dependence, which describes sentimentality
and sensitivity to others, and persistence, which includes
perseverance and industriousness, were reduced about
10 % by the substitution (main effect of 5-HT-2C on threeway ANOVA F (2,116) l 10.7, p 0.001). This effect
was markedly accentuated by the simultaneous presence
of the rarer 5-HT-2C and the rarer D4DR alleles ; for
example, reward dependence was 14.1 (.. 0.7) in 30
subjects with the common 5-HT-2C allele and long D4DR
alleles, and 8.0 (.. 2.0) in the 3 subjects with long D4DR
alleles, who were also homozygous for the rare 5-HT-2C
allele (Figure 2). This provocative effect size amounts to
about 10 times the pooled mean standard error of the
study population. However, in the light of the rarity of
Genes for personality traits
159
Table 3. Population associations between D3DR genotype and personality traits
Traits
D3 1,1
(n l 60)
D3 1,2
(n l 57)
D3 2,2
(n l 7)
p value
Novelty seeking
Harm avoidance
Persistence
Reward dependence
16.2 (4.9)
11.6 (5.8)
5.4 (1.5)
13.8 (3.3)
16.1 (5.3)
13.3 (5.9)
4.6 (2.3)
14.1 (3.5)
16.3 (4.3)
14.9 (5.3)
5.4 (2.9)
12.4 (3.2)
0.99
0.17
0.09
0.43
MANOVA : Wilk’s lambda l 0.92, df l 8, 236, overall p value l 0.27.
Modified from Ebstein et al. (1997e).
Figure 2. The effect of the 5-HT2C serotonin receptor
polymorphism on reward dependence (RD 1–4 and RD123)
and persistence (RD2) in subjects with the long D4DR exon
III repeat allele.
this combination, and the consequently small n with this
combination, the finding is necessarily preliminary. Moreover, it was not found in the American subjects described
above (Hamer, personal communication) ; this may reflect
the different instruments used, or genetic heterogeneity,
or true non-replication.
Allelic variation in functional 5-HT transporter
expression, anxiety-related personality traits and
susceptibility to affective disorders
The 5-HT transporter (5-HTT) is another interesting piece
in the mosaic-like texture of personality. Recent advances
have resulted from the functional and molecular characterization of the 5-HTT, from pharmacologic studies
relating the actions of psychoactive drugs (for example,
tricyclics, selective 5-HT reuptake inhibitors (SSRIs),
psychostimulants), to discrete effects on 5-HT uptake and
release, and from the molecular dissection of the complex
changes in functional expression as a consequence of
altered gene transcription. Elucidation of 5-HTT structure
has provided the means for studying 5-HT uptake
processes in humans at the molecular level (Lesch et al.,
1993). Progress has also been made in the dissection of
the 5-HTT’s genomic organization including 5’-flanking
transcriptional regulatory sequences, as well as in modelling 5-HTT-related brain dysfunction in mice by
targeted disruption of the 5-HTT gene. The influence of
genetic and environmental factors on 5-HTT function and
its impact on event-related synaptic plasticity in disease
and therapeutic intervention is of particular interest.
Highest densities of 5-HTT are found on serotonergic cell
bodies in the midbrain raphe complex and in its projection
areas including cortical areas, entorhinal cortex, CA3
region of the hippocampus, amygdala, substantia nigra,
caudate putamen, and hypothalamus. 5-HTT-dependent
functions are likely to play a meaningful role in developmental neuroplasticity, thus determining the expression of complex traits and their associated behaviour
throughout adult life (Lesch et al., 1996b). In this regard,
anxiety-related traits like ‘ neuroticism ’ on the NEO
questionnnaire, ‘ tension ’ on the 16PF and ‘ harm avoidance ’ on the TPQ are excellent examples of fundamental,
enduring, and continuously distributed dimensions of
normal personality. Although twin studies have indicated
that individual variation in measures of anxiety-related
traits are 40–60 % heritable, none of the relevant genes
has yet been identified. Moreover, it is becoming
increasingly evident that allelic variation of 5-HTT
activity, together with inadequate adaptive responses to
environmental stressors, are likely to contribute significantly to the aetiopathogenesis of affective disorders,
such as depression and manic-depressive illness.
5-HTT function appears to be dysregulated in a variety
of complex behavioural traits and disorders such as
depression, bipolar, anxiety, obsessive–compulsive,
schizophrenic, and neurodegenerative disorders, substance abuse and eating disorders (for review, see Ellis et
al., 1994 ; Owen et al., 1994). Moreover, 5-HT uptake
capacity has been proposed to be a trait variable for
affective disorder, since it remains decreased after recovery. Twin studies suggest that 5-HT uptake is
genetically controlled (Meltzer et al., 1988), which is
supported by the fact that 5-HTT function is lower in firstdegree relatives of patients with depression who them-
160
J. Benjamin et al.
selves display decreased 5-HT uptake. The hypothesis
that genetic control of and disease-related alteration in
5-HTT function is more likely to be related to differential
regulation of 5-HTT expression than to amino acid
substitutions, is further supported by the fact that
mutation-screening of the gene’s translated exons in
several samples of patients with affective spectrum and
obsessive-compulsive disorders (OCD) detected only rare
coding variants (Altemus et al., 1996 ; Di Bella et al., 1996 ;
Lesch et al., 1995). This led the present group to the search
for regulatory sequence variations that might modify the
expression rather than the structure of the transporter
protein. The human 5-HTT gene is composed of 14 exons
spanning " 35 kb (Lesch et al., 1994) and comparison of
the human and murine 5-HTT genes revealed a striking
conservation of both the exon\intron organization and
the 5h-flanking regulatory sequences (Bengel et al., 1997).
A common insertion\deletion polymorphism is located in
the transcriptional control region upstream of the 5-HTT
coding sequence (Heils et al., 1996).
Characteristics of the 5-HTT-linked polymorphic
region (5-HTTLPR)
The 5-HTTLPR is located approximately 1 kb upstream
of the 5-HTT gene transcription initiation site in a GCrich region and is composed of 14–16 repeat elements
with the consensus sequence CCCCCCTGCACCCCCCAGCAT. The polymorphism, which consists of the
presence or absence of a 44 bp segment involving repeat
element 6–8, is highly prevalent. PCR-based genotype
analysis of 505 American volunteers revealed allele
frequencies of 57 % for the long (l) allele and 43 % for the
short (s) allele. The 5-HTTLPR genotypes were distributed according to Hardy–Weinberg equilibrium : 32 %
l\l, 49 % l\s, and 19 % s\s. Although other variations,
such as rare single nucleotide substitutions, have been
detected within 5’-flanking promoter region (G. Stober
and K.-P. Lesch, manuscript in preparation), it remains to be
clarified whether these sequence variants affect promoter
activity.
Comparison of the 5-HTT gene promoter in different
species revealed that the 5-HTTLPR is ‘ foreign ’ DNA,
possibly of viral origin and unique to humans and nonhuman primates, including rhesus monkeys (Bengel et al.,
1997 ; A. Heils and K.-P. Lesch, unpublished observations).
The 5-HTTTLPR displays a complex G string-dependent
tetrastrand-like structure, silences transcriptional activity
in non-serotonergic cells, and contains positive response
elements (Heils et al., 1995). In addition, the 5-HTTLPR
confers allele-dependent differential transcriptional activity on 5-HTT gene promoter activity when fused to a
luciferase reporter gene and transfected into human
placental choriocarcinoma (JAR) cells (Heils et al., 1996).
Cyclic AMP- and protein kinase C (PKC)-dependent
mechanisms induced transcriptional activity in both
variants of the 5-HTT promoter, but the dose-dependent
increase following induction remained proportionally
smaller in the allele with the deletion.
Allelic variation of functional 5-HTT expression
Lesch et al. (1996a) determined the effects of 5-HTTLPR
variability on functional gene expression by studying the
relationship between 5-HTTLPR genotype, 5-HTT gene
transcription, and 5-HT uptake activity in human lymphoblastoid cell lines. Because appropriate cell models for
human serotonergic neurons do not exist and the JAR
cells are homozygotic for the 5-HTTLPR, lymphblastoid
cells represent a feasible compromise and cell lines with
the complete range of different 5HTTLPR genotypes can
readily be obtained. The effect of the 5-HTTLPR on
transcriptional activity was first assessed by transfecting
lymphoblastoid cells with constructs in which a luciferase
reporter gene was fused to " 1.4 kb of 5h-flanking
sequences (subsequently referred to as the 5-HTT promoter) containing the l or s form of the 5-HTTLPR.
Comparison of the allelic variants revealed that the basal
activity of the l variant was significantly higher than the
s form of the 5-HTT promoter, thus confirming our
findings in JAR cells. Activation of adenylyl cyclase with
forskolin or stimulation of PKC by a phorbol esterinduced transcriptional activity in both the l and s variants,
but the dose-dependent increase following induction of
cAMP- and PKC-dependent mechanisms remained
proportionally smaller in the s promoter variant.
Although transfection experiments with reporter gene
constructs are useful in assaying the transcriptional
competence of cloned promoter DNA sequences, they
could lead to false results due to the absence of more
distant control elements. Therefore, the present group
next studied the expression of the native 5-HTT gene in
lymphoblastoid cell lines with different 5-HTTLPR
genotypes. Cells homozygous for the l form of the 5-HTT
promoter showed significantly higher 5-HTT expression
and 5-HT uptake activity than did cells containing one or
two copies of the s variant. The genotype-dependent
differences in functional 5-HTT expression persisted
proportionally when 5-HTT gene transcription was
induced with forskolin or phorbol ester.
Association between the 5-HTTLPR and anxietyrelated traits
To determine the contribution of 5-HTTLPR variability to
individual phenotypic differences in personality traits, a
combined population and family genetic study in an
Genes for personality traits
161
Table 4. Population association between 5-HTT genotype and anxiety- and depression-related personality facets ; NEO-PI-R
T-scores (meanj..) (n l 505)
Group
L (n l 163)
(genotype l\l)
S (n l 342)
(genotype l\s or s\s)
F ratio
NEO domains
N Neuroticism
E Extraversion
O Openness
A Agreeableness
C Conscientiousness
53.1j11.5
54.2j10.6
59.4j11.6
48.2j10.7
45.9j10.9
56.4j11.8
53.0j11.1
58.1j11.3
46.1j11.6
44.8j12.3
9.3
1.4
1.3
4.0
1.0
3.3
k1.2
k1.3
k2.1
k1.1
0.002
ns
ns
0.045
ns
Neuroticism facets
N1 Anxiety
N2 Angry hostility
N3 Depression
N4 Self-consciousness
N5 Impulsiveness
N6 Vulnerability
52.5j11.6
50.5j10.8
52.3j11.0
53.0j11.1
54.1j11.0
51.6j10.9
54.9j11.6
53.9j11.6
55.3j11.8
54.3j11.9
56.9j10.9
52.8j11.3
4.9
9.9
7.3
1.4
7.0
1.3
2.4
3.4
3.0
1.3
2.8
1.2
0.027
0.002
0.007
ns
0.008
ns
S-L
p value
F, F value for one-way ANOVA comparing S and L genotype groups.
S-L, Mean score for S genotypes (s\s and s\l) minus mean score for L genotypes (l\l).
ns, not significant (p 0.05).
From Lesch et al. (1996b).
extended American sample totalling 505 subjects was
conducted (Lesch et al., 1996a) ; this sample was recruited
in the same manner as the sample described in Benjamin et
al. (1996b). Anxiety-related and other personality traits
were assessed by the NEO-PI-R. There was a significant
association between 5-HTTLPR genotype and NEO
‘ neuroticism ’ (Table 4). Individuals with either one or two
copies of the s form of the 5-HTT promoter (subsequently
referred to together as group S) had higher ‘ neuroticism ’
scores than individuals homozygous for the l variant of
the 5-HTTLPR (referred to as group L). The scores for the
l\s and s\s genotypes were not significantly different,
indicating that the polymorphism has more of a
dominant\recessive than of a codominant\additive effect
on neuroticism, just as it does on 5-HTT gene expression.
The distributions of ‘ neuroticism ’ scores in the S and L
groups were overlapping but had means that were
separated by 3.4 T score units, a difference of 0.29
.. units (Table 4 and Figure 3). The effect of the
5-HTTLPR genotype on personality was specific for
neuroticism. Scores on three of the other five major NEO
personality factors, ‘ extroversion ’, ‘ openness ’ and
‘ conscientiousness ’, were not significantly associated with
the genetic variant.
The 16PF questionnaire was used as a secondary
psychometric instrument. A significant and specific association between 5-HTTLPR genotype and the 16PF
‘ anxiety ’ factor was found ; this was primarily due to
associations with the two ‘ anxiety’-related 16PF traits of
‘ tension ’ and ‘ suspiciousness ’. The final method of
personality assessment was based on Cloninger’s biosocial
model. Although our subjects did not complete the TPQ,
it was possible to estimate TPQ scores from the NEOPI-R data using weighted regression equations. The
5-HTTLPR genotype was found to be associated with
estimated scores for ‘ harm-avoidance ’ but not the other
three TPQ traits. Analysis of the subscales for ‘ harmavoidance ’ showed significant associations with the scales
for ‘ worry and pessimism ’, ‘ fear of uncertainty ’ and
‘ fatiguability ’, but not to ‘ shyness ’. These results indicate
that the 5-HTTLPR influences a pattern of traits related
to anxiety. Across the three personality measures, the
5-HTT polymorphism contributes a moderate 7–9 %
of the genetic variance, based on estimates from twin
studies using these and related measures.
The association between 5-HTTLPR genotype and
personality traits was then analysed in 78 sib-pairs that
were discordant for the 5-HTTLPR. Despite the reduction
in sample size, the difference between the L and S siblings
was statistically significant even after conservatively
correcting for the non-independence of sib-pairs from the
same family. These family studies show that the observed
associations between 5-HTTLPR genotype and anxietyrelated traits are due to genetic transmission rather
than population stratification. Overall, however, the
associations reported here represent only a small portion
of the genetic contribution to anxiety-related traits
observed in this non-random population sample.
162
J. Benjamin et al.
Table 5. Genotype and allele frequency of the 5-HT transporter-linked polymorphic
region (5-HTTLPR) in affective disorders
Controls
(n l 570)
Combined
affective
disorder
(n l 454)
Bipolar
disorder
(n l 304)
Unipolar
depression
(n l 150)
(a) Genotype
l\l
l\s
s\s
191 (33 %)
278 49 %)
101 (18 %)
128 (29 %)
211 (46 %)
115 (25 %)
χ# l 9.5,
p l 0.009
82 (27 %)
148 (49 %)
74 (24 %)
χ# l 6.4,
p l 0.04
46 (31 %)
63 (42 %)
41 (27 %)
χ# l 6.2,
p l 0.05
(b) Allele
l
s
660 (58 %)
480 (42 %)
467 (51 %)
441 (49 %)
χ# l 8.5,
p l 0.004
312 (51 %)
296 (49 %)
χ# l 7.0,
p l 0.008
155 (52 %)
145 (48 %)
χ# l 3.8,
p l 0.05
From Collier et al. (1996b).
dosage effects to anxiety, approximately 10–15 genes
might be predicted to be involved.
Since the original observation, a number of similar
studies have continued to explore the influence of the 5HTTLPR (Ball et al., 1997 ; Ebstein et al., 1997b ; Nakamura
et al., 1997 ; Ricketts et al., 1997) and other polymorphisms
(Evans et al., 1997) at the 5-HTT gene locus on anxietyrelated traits. Ricketts et al. confirmed the association,
while the other three studies of the 5-HTTPLR did not.
Thus this association, like the D4DR – novelty-seeking
association, cannot be considered definitive.
Figure 3. Distributions of neuroticism (NEO-PI-R factor N)
scores. The x axis shows the neuroticism scores separated
into 8 groups with the indicated median T scores. The y axis
shows the distribution, in percent, of subjects with short
5-HTT alleles (group S, n l 342, empty bars), and the
distribution, in percent, of subjects with long 5-HTT alleles
(group L, n l 163, solid bars).
There is considerable evidence indicating that increased
serotonergic neurotransmission (which would be an
evident consequence of the reduced 5-HT uptake capacity
found in individuals with short 5-HTTLPR alleles) is
anxiogenic in animal models as well as in humans. At the
clinical level, reduced 5-HT uptake or reduced inhibitor
binding to the 5-HTT has been one of the most consistent
psychobiological findings in individuals with depression
and several anxiety disorders. The associations reported
here represent only a small portion of the genetic
contribution to anxiety-related personality traits. If other
genes were hypothesized to contribute similar gene-
D4DR and 5-HTTLPR in neonates
Neonatal infants are at a phase of development when
environmental influences are minimal and least likely to
confound associations between temperament and genes.
The possible influence of D4DR and\or 5-HTTLPR on
temperament in 2-wk-old human infants was evaluated
using the Brazelton neonatal assessment scale (Ebstein et
al., 1997c). D4DR was associated most significantly with
the cluster of items termed ‘ orientation ’, that is, attention
to novel stimuli. The homozygous short 5-HTTLPR
genotype lowered orientation scores in infants who also
lacked a long D4DR allele. We may speculate that
‘ orientation ’ is a prima facie neonatal equivalent of
novelty-seeking, and that, in the absence of its enhancement by a long D4DR allele, it is opposed by a
genotype which acts to increase the neonatal equivalent
of anxiety, neuroticism or harm avoidance.
Genes for personality traits
163
Figure 4. Low functional expression of the serotonin transporter as a susceptibility factor for affective spectrum disorders.
5-HTT expression and susceptibility to affective
disorders
Genetic susceptibility factors contribute to the aetiology
of affective illness, including bipolar affective disorder and
unipolar depression, and heritability is estimated to be up
to 86 % for bipolar disorder (McGuffin et al., 1994) and
30 to 37 % for depression (Kendler et al., 1994).
Although both disorders may share factors which determine depressive symptomatology with an associated
high risk of suicide (Winokur et al., 1995), genetic
heterogeneity and a substantial but varying environmental component complicates identification of predisposing genes.
To test the influence of 5-HTTLPR-dependent variability in functional 5-HTT expression on susceptibility to
affective illness, a genetic case-control study was performed on independently ascertained samples from 3
different European centres (Collier et al., 1996b). English
(n l 277) and German (n l 86) subjects satisfied DSMIV criteria for bipolar I disorder or major depression ;
Italian subjects (n l 97) satisfied DSM-III-R criteria for
the same disorders. Table 5 shows the allele and genotype
frequencies in the affected subjects (n l 570) versus the
controls (n l 454). When the data for each centre were
analysed separately, no significant differences were found
in the allele or genotype frequencies of the 5-HTTLPR
between cases and controls for any diagnosis, although
there was an excess of the low-activity allele (short 5HTTLPR) over the high activity allele (long 5-HTTLPR)
for affected subjects from all countries (Table 5). When all
samples were combined by diagnosis, there was a
significant excess of the low activity allele in both bipolar
affective disorder (n l 304 ; p l 0.008) and unipolar
depression (n l 150 ; p l 0.05) in comparison to controls
(n l 570). Significant differences were also found in the
genotype frequencies of the 5-HTTLPR between cases
and controls for both diagnoses. Differences in genotype
and allele frequencies were most significant for the
combined affective disorders category (n l 454 ; p l
0.009 and p l 0.004, respectively). There was no statistical evidence for heterogeneity of samples between
centres for either patients or controls. The odds ratio (OR)
and relative risk (RR) for the association of the lowactivity allele with the combined affective disorders were
similar and both indicated a relative risk of 1.7-fold for
homozygotes for the short 5-HTTLPR variant, whereas
the effect in heterozygotes did not reach significance (RR,
1.14). The population-attributable risk (AR) resulting from
the low-activity allele was calculated to be 9 % (5 %
confidence interval, 2.7–16.3 %) for the combined affective
disorders category.
Linkage between the 5-HTT locus on human chromosome 17q12 and bipolar affective disorder has not been
detected, although individual families with lod scores of
approximately 1 have been observed (Kelsoe et al., 1996).
This is not necessarily unexpected, since linkage analysis
does not have the sensitivity to detect quantitative trait or
vulnerability loci with modest effects ; nevertheless,
linkage would bolster confidence in the association
finding. Previous analysis of the 5-HTT gene for polymorphic variants revealed, in addition to some rare
polymorphisms which were not associated with affective
disorders (Altemus et al., 1996 ; Di Bella et al., 1996 ; Lesch
et al., 1995), a VNTR located in intron 2 with two
common (with 10 or 12 repeats) and one rare allele (with
9 repeats) (Lesch et al., 1994). This rare allele was reported
to be associated with unipolar but not bipolar affective
disorder (Ogilvie et al., 1996). While this finding has not
been replicated (Collier et al., 1996a ; Stober et al., 1996),
analysis of a larger sample of subjects with affective
disorders indicated a strong association between allele 12
164
J. Benjamin et al.
and bipolar disorder (Collier et al., 1996a). The allelic
association between the intron 2 VNTR and affective
disorders in these studies does not appear to be entirely a
result of linkage disequilibrium between the two polymorphisms, since only modest evidence for linkage
disequilibrium between the intronic VNTR and 5HTTLPR in a subsample was detected (Collier et al.,
1996b).
Our findings indicate the low transporter-mediated 5HT uptake function resulting from reduced activity of the
5-HTT gene’s transcriptional apparatus increases susceptibility to both bipolar affective disorder and unipolar
depression. Although the increase in risk for homozygotes
for the low 5-HT uptake activity allele is relatively
modest, the observation of a similar effect of this allele in
both unipolar depression and bipolar disorder may
indicate that affective spectrum disorders share a general
genetic susceptibility locus for anxious and depressive
symptoms (Figure 4). To further validate the concept of
the 5-HTT gene as a susceptibility locus for anxiety- and
depression-related symptomatology this group is currently pursuing a transgenic strategy (Bengel et al., 1996).
This approach addresses the question to what extent
targeted disruption of the 5-HTT gene affects biochemistry, electrophysiology and pharmacology of the 5-HT
system and modulates neural development and synaptic
plasticity. It also may provide a system to dissect
successive events that lead to disease states related to
anxiety and depression as well as to test novel therapeutic
concepts.
Conclusion
The difficulties of finding genes directly responsible for
psychiatric disorders have been discussed and evidence
presented for the possibility that normal personality traits,
extreme deviations of normal personality traits (personality disorders), and mental illnesses may represent
differing positions on a genetic continuum.
Following preliminary studies which indicated the
importance of investigating genes for normal personality,
a direct and replicated genetic association was reported
between a candidate gene for a receptor of undoubted
relevance to psychiatry, the dopamine D4 receptor, and
the normal personality trait of novelty-seeking. A possible
marked effect of an interaction between two genes on the
trait of reward dependence was also reported. Moreover,
the 5-HTT gene, thought to be a site of action of 5-HT
reuptake blocking antidepressants, was cloned and characterized ; a functional polymorphism in the promoter region
of the gene was described, as was an association between
this polymorphism and anxiety-related personality traits.
Evidence for possibly equivalent effects was also seen in
neonates. Finally, there is evidence that allelic variation in
functional 5-HTT expression may be a susceptibility
factor for disorders of the affective spectrum.
We believe that both normal personality traits and
psychiatric disorders are amenable to genetic study, and
that the genetic component of the former may contribute
to the latter. The task ahead is to demonstrate the links
between these and other genetic findings in personality
disorders and psychiatric illnesses. The work described so
far elevates this objective from the status of a scientific
hypothesis to that of an ongoing research programme.
Acknowledgements
The work of the following collaborators is gratefully
acknowledged : R. Alexander, M. Baron, R. H. Belmaker,
D. Bengel, E. R. Bennett, D. Blaine, B. D. Greenberg, D. H.
Hamer, A. Heils, M. Katz, B. Lerer, L. Li, B. Maoz, R.
Moessner, C. R. Mueller, D. L. Murphy, L. Nemanov, O.
Novick, Y. Osher, C. Patterson, J. Press, B. Priel, S. Z.
Sabol, R. Umansky. K. P. Lesch is supported by the
Hermann and Lilly Schilling Foundation.
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