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Evidence for a common biological basis of the absorption trait hallucinogen effects and positive symptoms Epistasis between 5-HT2a and COMT polymorphisms.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 137B:29 –32 (2005)
Brief Research Communication
Evidence for a Common Biological Basis of the Absorption
Trait, Hallucinogen Effects, and Positive Symptoms:
Epistasis Between 5-HT2a and COMT Polymorphisms
Ulrich Ott,1* Martin Reuter,1 Juergen Hennig,1 and Dieter Vaitl1,2
1
Center for Psychobiology and Behavioral Medicine, University of Giessen, Germany
Department of Clinical and Physiological Psychology, University of Giessen, Germany
2
Absorption represents a disposition to experience
altered states of consciousness characterized by
intensively focused attention. It is correlated with
hypnotic susceptibility and includes phenomena
ranging from vivid perceptions and imaginations
to mystical experiences. Based on the assumption that drug-induced and naturally occurring
mystical experiences share common neural mechanisms, we hypothesized that Absorption is influenced by the T102C polymorphism affecting the
5-HT2a receptor, which is known to be an important target site of hallucinogens like LSD. Based
on the pivotal role ascribed to the prefrontal
executive control network for absorbed attention
and positive symptoms in schizophrenia, it was
further hypothesized that Absorption is associated with the VAL158MET polymorphism of the
catechol-O-methyltransferase (COMT) gene affecting the dopaminergic neurotransmitter system.
The Tellegen Absorption Scale was administered
to 336 subjects (95 male, 241 female). Statistical
analysis revealed that the group with the T/T
genotype of the T102C polymorphism, implying a
stronger binding potential of the 5-HT2a receptor,
indeed had significantly higher Absorption scores
(F ¼ 10.00, P ¼ 0.002), while no main effect was
found for the COMT polymorphism. However,
the interaction between T102C and COMT genotypes yielded significance (F ¼ 3.89; P ¼ 0.049), underlining the known functional interaction
between the 5-HT and the dopaminergic system.
These findings point to biological foundations of
the personality trait of Absorption.
ß 2005 Wiley-Liss, Inc.
KEY WORDS:
molecular genetics; absorption
trait; T102C; serotonin; dopamine
The personality trait of Absorption represents ‘‘an openness
to absorbing and self-altering experiences’’ correlated with
*Correspondence to: Ulrich Ott, Center for Psychobiology and
Behavioral Medicine, University of Giessen, Otto-BehaghelStreet 10F, 35394 Giessen, Germany.
E-mail: Ulrich.Ott@psychol.uni-giessen.de
Received 6 December 2004; Accepted 21 April 2005
DOI 10.1002/ajmg.b.30197
ß 2005 Wiley-Liss, Inc.
hypnotic susceptibility [Tellegen and Atkinson, 1974]. The
items of the Tellegen Absorption Scale [Tellegen, 1982] describe strong emotional responses to the beauty of nature, music
and poetry, synesthetic impressions, paranormal experiences,
thinking in images, absorbed attending to movies or plays,
vivid memories and daydreams, and a mystical widening of
consciousness. A core feature of this wide variety of experiences is a special kind of focused attention wherein it appears
that one phenomenal object occupies all representational resources: ‘‘objects of absorbed attention acquire an importance
and intimacy that are normally reserved for the self and may,
therefore, acquire a temporary self-like quality. These object
identifications have mystical overtones. And, indeed, one would
expect high-Absorption persons to have an affinity for mystical
experience. . .’’ [Tellegen and Atkinson, 1974].
Recently, it has been proposed that LSD and nondruginduced mystical experiences share common neural mechanisms related to the serotonergic neurotransmitter system
[Goodman, 2002]. There is converging evidence that the site
of action of LSD is the 5-HT2a receptor [Aghajanian and
Marek, 1999; Nichols, 2004]. Thus, inter-individual differences
in the disposition to experience mystical states of consciousness could be based, at least in part, on the binding potential of
serotonergic receptors. A similar hypothesis was formulated by
Borg et al. [2003], who found in a positron emission tomography (PET) study a significant association between the
binding potential of 5-HT1A receptors and spiritual experiences, assessed with the scale ‘‘self-transcendence’’ of the
temperament and character inventory [Cloninger et al., 1994].
The phenomena included in the Absorption scale show
striking similarities to alterations of consciousness reported
after LSD ingestion, namely fascination and absorption by
perceptual or imaginational objects, synesthesia, and mystical
states. Consequently, it was hypothesized that the proneness
to Absorption was mediated partly by the serotonergic system.
In order to test this hypothesis, an approach from molecular
genetics was used to test for associations between the trait of
Absorption and a candidate gene of the serotonergic system.
The T102C polymorphism of the 5-HT2a gene was chosen due
to its relevance for the pharmacological effects of LSD
[Aghajanian and Marek, 1999; Nichols, 2004] and due to reported associations with schizophrenia [Williams et al., 1996;
Abdolmaleky et al., 2004]. Positive symptoms in schizophrenic
patients resemble hallucinations induced by psychostimulants
and could be considered as extreme form of Absorption phenomena observed in healthy individuals. The 5-HT2A T102C
marker located on chromosome 13 q14-q21 is a silent single
nucleotide polymorphism (SNP) so that the C to T substitution
does not alter the amino acid sequence and therefore the receptors encoded by the ‘‘C’’ and ‘‘T’’ allele are identical.
30
Ott et al.
However, the 5-HT2a T102C polymorphism has been shown to
be associated with numerous psychopathologies including
schizophrenia [Polesskaya and Sokolov, 2002] indicating that
this SNP is a marker polymorphism being in linkage with
another still unidentified gene locus which is of functional
relevance. The prevalence of the T- and C-allele in Caucasian
populations is about 0.41 and 0.59, respectively [Bondy et al.,
2000]. It was expected that the group with the T/T genotype of
the T102C polymorphism would obtain higher Absorption
scores, since a lower receptor binding in carriers of the C-allele
of the 5-HT2a polymorphism has been revealed in a PET study
[Turecki et al., 1999].
The close connection of Absorption with hypnotic susceptibility was the starting point for a second line of reasoning.
Neuroscientific approaches to the hypnotic process emphasize
the superior ability of highly hypnotizable subjects to regulate their attention [Crawford, 1994]. In a PET study, mental
absorption during hypnosis was found to be correlated with
increased activity in the anterior cingulate cortex (ACC)
[Rainville et al., 2002]. The ACC is the key structure of the
executive control network and a target area of the dopaminergic (DA) system [Raz and Shapiro, 2002]. Indeed,
an association was found between hypnotic susceptibility
and the catechol-O-methyltransferase (COMT) polymorphism
[Lichtenberg et al., 2000]. COMT is an enzyme, which has a
crucial role in the metabolism of catecholamines by inactivating them in the synaptic cleft. A SNP, a G!A transition in
codon 158 of the COMT gene located at the q11 band of human
chromosome 22, results in three to fourfold difference in COMT
enzyme activity [Lachman et al., 1996] by coding for the synthesis of the amino acid methionine (MET) instead of valine
(VAL). Heterozygotes (VAL/MET genotype) have intermediate
levels of COMT activity [Lachman et al., 1996; Syvänen et al.,
1997]. The prevalence of the MET and the VAL allele is about
50% in Caucasian populations.
The Absorption scale was also administered in the study by
Lichtenberg et al. [2000]. While Absorption was significantly
correlated with hypnotic susceptibility, no relationship of
Absorption with the COMT polymorphism was observed. However, there was a trend for individuals with the MET/MET
genotype to obtain lower Absorption scores, which did not
reach significance due to the high variance of the scores and the
low sample size (N ¼ 109).
Therefore, it was hypothesized that inter-individual differences in the capacity for absorbed attention were also influenced by genetic variations affecting the DA system. In order to
test this hypothesis, the association between the trait of
Absorption and the COMT polymorphism was investigated. A
trend similar to that reported above [Lichtenberg et al., 2000]
was expected. Interactions between the polymorphisms were
tested because on the one hand 5-HT inhibits DA release via
5-HT2a postsynaptic receptors [e.g., Porras et al., 2002] and on
the other hand hallucinations in schizophrenic patients which
resemble effects of LSD and other hallucinogens can be reduced by typical antipsychotics which are DA-antagonists.
Yet, a study on the influence of the DA-antagonist haloperidol on psychological effects of the hallucinogen psilocybin
[Vollenweider et al., 1998] found that only some effects were
reduced (derealization and depersonalization), while others
were left unchanged (illusions, pseudo-hallucinations, synesthetic phenomena) or even enhanced (thought disorder,
anxious ego-disintegration). Therefore, we had no directed
hypothesis about the interaction between the 5-HT2a and the
COMT polymorphism.
The Tellegen Absorption Scale (TAS) was administered
to 336 subjects (95 male, 241 female; age: M ¼ 24.7, SD ¼
5.6 years), mostly students of the University of Giessen,
Germany. In order to improve the psychometric properties of
the TAS, the response format of the German version [Ritz and
Dahme, 1995] has been changed from the original dichotomous
format (‘‘True’’ or ‘‘False’’) to a five-point scale ranging from
‘‘does not apply’’ to ‘‘does fully apply’’ (coded as item scores from
0 to 4).
DNA was extracted from buccal cells to avoid a selective
exclusion of subjects with blood and injection phobia. Purification of genomic DNA was performed with a standard
commercial extraction kit (High Pure PCR Template Preparation Kit; Roche Diagnostics, Mannheim, Germany). Genotyping of the 5-HT2a T102C and the COMT VAL158MET
polymorphisms was performed by real time PCR using fluorescence melting curve detection analysis by means of the
Light Cycler System (Roche Diagnostics). The primers and
hybridization probes used (TIB MOLBIOL, Berlin, Germany)
and the PCR protocols were as follows.
5-HT2a: forward primer: 50 -CTTATATGTGTGAGTCTGAGTGG-30 ; reverse primer: 50 -CCATGATGACGAGTATGTTT-30 ;
anchor hybridization probe: 50 -LCRed640-CTTCTGATGCATTTAACTGGACAGTCG-phosphate-30 ; sensor hybridization
probe: 50 -GACTTTAACTCCGGAGAAGCTAAC-fluorescein-30 .
The PCR run comprised 55 cycles of denaturation (958C, 0 sec,
ramp rate 208C/sec), annealing (608C, 10 sec, ramp rate 208C/
sec), and extension (728C, 10 sec, ramp rate 208C/sec) which
followed an incubation period of 10 min to activate the
FastStart Taq DNA Polymerase of the reaction mix (Light
Cycler FastStart DNA Master Hybridization Probes, Roche
Diagnostics). After amplification, a melting curve was generated by holding the reaction time at 408C for 2 min and then
heating slowly to 958C with a ramp rate of 0.28C/sec. The
fluorescence signal was plotted against temperature to yield
the respective melting points (Tm) of the two alleles. Tm for the
T allele was 56.808C and 63.408C for the C allele.
COMT: forward primer: 50 -GGGCCTACTGTGGCTACTCA30 ; reverse primer: 50 -GGCCCTTTTTCCAGGTCTG-30 ; anchor
hybridization probe: 50 -LCRed640-TGTGCATGCCTGACCCGTTGTCA-phosphate-30 ; sensor hybridization probe: 50 -ATTTCGCTGGCATGAAGGACAAG-fluorescein-30 . The PCR run
comprised 55 cycles of denaturation (958C, 0 sec, ramp rate
208C/sec), annealing (578C, 10 sec, ramp rate 208C/sec), and
extension (728C, 10 sec, ramp rate 208C/sec) which followed an
incubation period of 10 min to activate the FastStart Taq DNA
polymerase of the reaction mix. After amplification, the melting points were determined as described above. Tm for the VAL
allele was 59.008C and 64.508C for the MET allele.
The study was approved by the ethics committee of the
German Association of Psychology and written informed consent was obtained from all participants.
The Absorption scores of our sample were in good agreement
with the normative data reported for the German version of the
TAS [Ritz and Dahme, 1995], including the gender difference,
that is, slightly lower scores for males (Table I). In contrast to
the normative data, this difference did not reach significance in
our sample.
The genotype distributions for the T102C SNP of the 5-HT2a
gene and the VAL158MET SNP of the COMT gene were in
Hardy–Weinberg Equilibrium (see Table II).
TABLE I. Means (SD) of the Absorption Scores* and Normative
Data [Ritz and Dahme, 1995]
Gender
Sample (N ¼ 336)
Normative data (N ¼ 252)
Male
Female
Total
59.23 (22.17) (N ¼ 95)
63.69 (21.59) (N ¼ 241)
62.43 (21.82)
55.37 (19.91) (N ¼ 131)
66.29 (19.45) (N ¼ 121)
60.05 (19.98)
*Note: The scores reported here are higher than those reported by
Lichtenberg et al. [2000] because of the polychotomous response format of
the German version of the Absorption scale (see text).
Absorption: Epistasis Between 5-HT2a and COMT
31
TABLE II. Frequencies of the two Determined Polymorphisms (T102C, COMT) and Absorption
Scores (AS) of the Genotypes
Genotypes
T/T
VAL/VAL
Incidence (%)
Mean AS (SD)
VAL/MET
Incidence (%)
Mean AS (SD)
MET/MET
Incidence (%)
Mean AS (SD)
Total
Incidence (%)
Mean AS (SD)
T/C
41 (12.2)
58.78 (23.64)
26 (7.7)
56.86 (15.39)
82 (24.4)
60.89 (22.68)
25 (7.4)
64.80 (24.91)
77 (22.9)
64.99 (22.50)
62 (18.5)
59.52 (20.13)
164 (48.8.)
60.22 (20.91)
19 (5.7)
68.20 (19.49)
41 (12.2)
60.39 (22.99)
30 (8.9)
61.85 (22.79)
90 (26.8)
60.38 (20.79)
59 (17.6)
68.00 (19.21)
159 (47.3)
59.37 (23.13)
118 (35.1)
57.85 (19.32)
336 (100.0)
60.46 (21.30)
90
Tellegen Absorption Scale [M±SEM]
Total
15 (4.7)
76.33 (16.45)
For the statistical analysis, based on theoretical considerations, subjects with one certain homozygous genotype were
tested against the subjects with the two remaining genotypes
grouped together. In the case of the T102C polymorphism, the
T/T genotype, implying a higher binding capacity [Turecki
et al., 1999], was tested against the T/C and C/C genotypes,
that is, carriers without the C-allele were tested against carriers of the C-allele. In the case of the COMT polymorphism,
the VAL/VAL genotype, implying an up to fourfold higher
catabolic enzyme activity [Lachman et al., 1996], was tested
against the VAL/MET and the MET/MET genotype because
the VAL/VAL genotype is associated with a vulnerability to
schizophrenia [Lachman et al., 1996] and the efficiency of the
frontal executive control system. While some studies reported
a less efficient executive control system associated with the
VAL-allele in schizophrenic patients [e.g., Goldberg et al.,
2003], also superior performance of executive attention was
found to be associated with the VAL/VAL genotype in healthy
subjects [Fossella et al., 2002].
Results of the two-way ANOVA 5-HT2a COMT showed
a significant main-effect with respect to the 5-HT2a SNP
(C-allele: F ¼ 10.00, P ¼ 0.002, Eta2 ¼ 0.029) and a significant
interaction COMT 5-HT2a (MET C-allele: F ¼ 3.89, P ¼
0.049, Eta2 ¼ 0.012). There was no main-effect with respect to
the COMT SNP (F ¼ 0.073, P ¼ 0.395, Eta2 ¼ 0.002). In total,
over 4% of the variance in Absorption was explained by these
two genes. Carriers of the TT-genotype showed significantly
higher TAS scores than subjects without a T-allele. Moreover,
TAS scores were highest in subjects who are homozygous for
the T-allele as well as for the VAL-allele of COMT (see Fig. 1).
The present study demonstrated, for the first time, an association between the personality trait of Absorption and two
85
80
75
T102C
70
T/T
C/C, C/T
65
60
55
50
45
40
MET/MET, VAL/MET
C/C
VAL/VAL
COMT
Fig. 1. Association of the trait of Absorption with genetic polymorphisms: Interaction between T102C and COMT genotypes.
polymorphisms that affect the serotonergic and the dopaminergic neurotransmitter systems and account together for over
4% of the variance in Absorption as measured by Tellegen’s
scale. Subjects homozygous for the T-allele, which is related to
a higher binding affinity of the 5-HT2a receptor [Turecki et al.,
1999], had significantly higher TAS scores. In addition, a
significant interaction between the 5-HT2a and the COMT
gene indicates that TAS scores were highest in subjects homozygous for the TT-genotype of 5-HT2a as well as for the VAL/
VAL genotype of COMT. Therefore, a high binding affinity of
the 5-HT2a gene and a high catabolic enzyme activity of COMT
are related to high Absorption. From a pharmacological point
of view, the reported interaction between two SNPs of the
5-HT2a receptor gene and the COMT gene is highly plausible because the 5-HT system exerts an inhibitory effect on
DA release via the 5-HT2a receptor [e.g., Porras et al., 2002].
The present results once more corroborate the assumption that
personality traits within a normal range and psychopathological disorders have one common underlying dimension
[Donnelly, 1998]: Phenomena of Absorption resemble—
although in a very mild form—positive symptoms observed in
schizophrenia and drug-induced hallucinations. Moreover,
LSD exerts its effects via the 5-HT2a receptor [Aghajanian
and Marek, 1999; Nichols, 2004], which showed a strong association with the trait of Absorption in our study. In the same
line, the COMT gene is related to hypnotic susceptibility in
healthy subjects [Lichtenberg et al., 2000] and to schizophrenia [Williams et al., 1996; Abdolmaleky et al., 2004]. While
hypnotizability was found to be significantly correlated with
Absorption, Lichtenberg et al. [2000] failed to detect a significant association of the COMT gene with Absorption. However,
the present study demonstrates that there is an association between COMT and Absorption, which is only revealed
through an epistasis effect with 5-HT2a.
It is well known that complex phenotypes of high heritability as personality traits are determined by many genes
(Quantitative Trait Loci, QTL) and not only by single gene
loci. Therefore, additional polymorphisms should be included
in further studies, for instance the dopamine D4 receptor gene
(DRD4) polymorphism, that was already found to be associated
with the scale ‘‘self-transcendence’’ of Cloninger’s temperament and character inventory (TCI-ST) [Comings et al., 2000].
On account of the moderate sample size (N ¼ 336), the reported
findings have to be interpreted cautiously and require replication. The reported interaction is mainly based on the
small group of subjects carrying the VAL/VAL- as well as the
TT-genotype. This combination of homozygous genotypes is
seldom in the population resulting in a cell frequency of n ¼ 15
in our sample. In order to replicate our findings greater gene
banks could focus selectively on these subjects to test for higher
Absorption scores.
32
Ott et al.
Nevertheless, several other studies provide additional evidence for a biological basis of Absorption and related personality
traits. In a twin study, including 4300 North Americans,
a broad-sense heritability (additive genetic variance þ
dominance variance) of Absorption of 26% for males and 44%
for females was found [Finkel and McGue, 1997]. The TCI-ST
contains many items similar to those of the TAS. Initially, the
TCI-ST was conceptualized as a character dimension thought
to be mainly a result of culture and learning. It turned out,
however, that it forms indeed a distinct genetic factor with an
estimated heritability of 39% [Ando et al., 2002].
Association studies like the present one provide further
pieces of the puzzle, that have to be fitted into models of brain
functioning of altered states of consciousness in general
[Dietrich, 2003] and of those induced by drugs or during acute
psychosis [Vollenweider and Geyer, 2001]. The role of the executive attention network for states of absorption has already
been mentioned in the introduction as well as the conflicting
results regarding the influence of the VAL-allele on its efficiency. In order to elucidate the actual brain regions responsible
for the personality differences, neuroimaging studies are needed that compare activation patterns of subjects with certain
genotypes during corresponding tasks. Such a combination of
molecular genetics with functional magnetic resonance imaging has already produced very promising results, indicating
that brain activation of the ACC during an attention test is
markedly influenced by polymorphisms affecting the dopamine neurotransmitter system (DRD4 and monoamine oxidase
A, MAO-A) [Fan et al., 2003].
In the same way, distinct states of absorption— for example,
induced by hypnotic audiovisual stimulation or concentrative
meditation—could be compared in subjects with specific
combinations of genotypes. The effects of specific polymorphisms on the local activation within neural networks seems to be
much stronger than their effects on behavioral or questionnaire measures, so that differences can be detected with considerably smaller samples [Fan et al., 2003]. The present study
indicates that there might be one underlying continuum for the
trait of Absorption and positive symptoms in schizophrenia.
Because complex syndromes like schizophrenia are likely
caused by multiple genes, the study of endophenotypes like
Absorption yield further insights into the genetic underpinnings of schizophrenia.
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