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T102C polymorphism in the 5HT2A gene and schizophrenia: Relation to

phenotype and drug response variability

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 PHARMACOGENETICS PHARMACOGENETIQUE
Research Paper / Artilde de recherche

T102C 5HT2A gene

polymorphism in the
and schizophrenia: relation to phenotype
and drug response variability
Ridha Joober, MD, PhD; Chawki Benkelfat, MD; Kateri Brisebois;
Andre Toulouse, PhD; Gustavo Turecki, MD; Samarthji Lal, MD;
David Bloom, MD; Alain Labelle, MD; Pierre Lalonde, MD; Diane Fortin;
Martin Alda, MD; Roberta Palmour, PhD; Guy A. Rouleau, MD, PhD

Joober Montreal General Hospital Research Institute, Douglas Hospital Research Centre, and McGill University
Department of Psychiatry; Benkelfat, Palmour McGill University Department of Psychiatry; Brisebois, Toulouse, Turecki,
Fortin, Rouleau Montreal General Hospital Research Institute; Lal, Bloom Douglas Hospital Research Centre,
Montreal, Que.; Labelle, Alda University of Ottawa and Royal Ottawa Hospital, Ottawa, Ont.; Lalonde University of
Montreal and L.H. Lafontaine Hospital, Montreal, Que.

Although genes play a major role in the etiology of schizophrenia, no major genes involved in this disease
have been identified. However, several genes with small effect have been reported, though inconsistently,
to increase the risk for schizophrenia. Recently, the 5HT2A 2 allele (T102C polymorphism) was reported
to be over-represented in patients with schizophrenia. Other reports have found an excess of allele 2(C)
only in schizophrenic patients who are resistant to clozapine, not in those who respond to clozapine. In
this study, the 5HT2A receptor allele 2 frequencies were compared between 2 groups of patients with
schizophrenia (39 responders and 63 nonresponders) based on long-term outcome and response to typi-
cal neuroleptics. A control group of 90 healthy volunteers screened for mental disorders was also includ-
ed. Genotype 2/2 tended to be more frequent in patients with schizophrenia with poor long-term outcome
and poor response to typical neuroleptics (Bonferroni corrected p = 0.09). This difference was significant
in men (Bonferroni corrected p = 0.054) but not in women. In addition, the age at first contact with psy-
chiatric care was significantly younger in the patients with schizophrenia with genotype 2/2 than in patients
with genotype I/1. These result suggest that the 5HT2A-receptor gene may play a role in a subset of schizo-
phrenia characterized by poor long-term outcome and poor response to neuroleptics.

Meme si les genes jouent un r6le important dans l'etiologie de la schizophrenie, on n'a pas identifie de genes
majeurs mis en cause dans cette maladie. On a toutefois signale, mais de fason irreguliere, que plusieurs genes
qui ont des effets limites augmentent le risque de schizophrenie. On a signale recemment que l'allele 5HT2A
2 (polymorphisme T 02C) etait surrepresente chez les patients atteints de schizophrenie. Dans d'autres cas,
on a constate la presence d'un surplus d'allele 2(C) seulement chez les patients schizophreniques qui resistent
a la clozapine, et non chez ceux qui y reagissent. Dans le cadre de cette etude, on a compare les frequences

Correspondence to: Dr. Ridha Joober, Douglas Hospital Research Centre, 6875 Boulevard LaSalle, Verdun QC H4H I R3; fax 514 888-
4064; rjoobe@po-box.mcgill.ca
Medical subject headings: alleles; drug resistance; genetics; genotype; pharmacogenetics; polymorphism (genetics); receptors, serotonin; schizophrenia
J Psychiatry Neurosci 1999;24(2): 141-6.
Submitted Aug. 19, 1998
Revised Oct. 1, 1998
Accepted Oct. 6, 1998
©) 1999 Canadian Medical Association

%0t600
It,
Vol. 24 no 2, 1"99
24, no 1999 Journal
ioumal of Psychiatry
Psy...&& Neuroscience
141

141
 joober et ail

3
a de l'allele 2 recepteur de 5HT2A entre deux groupes de patients atteints de schizophrenie (39 qui ont reagi et 63 qui
n'ont pas reagi) en fonction d'un resultat a long terme et de la reaction a des neuroleptiques typiques. On a aussi
inclus un groupe temoin de 90 volontaires en bonne sante chez lesquels on a depiste la presence de troubles men-
taux. Le genotype 2/2 avait tendance a etre plus frequent chez les patients atteints de schizophrenie dont les resul-
,0
tats a long terme etaient mediocres et la reaction aux neuroleptiques typiques etait mediocre (rajustement de
_
Bonferroni p = 0,09). Cette difference est importante chez les hommes (rajustement de Bonferroni p = 0,054), mais
V
non chez les femmes. En outre, l'age au premier contact avec des soins psychiatriques etait beaucoup bas chez les
ol
patients atteints de schizophrenie qui avaient le genotype 2/2 que chez ceux qui avaient le genotype I/ 1. Ces resul-
_

_.
tats indiquent que le gene recepteur de 5HT2A peut jouer un role dans un sous-ensemble de schizophrenie carac-
terisee par la mediocrite des resultats a long terme et de la reaction aux neuroleptiques.
r v

Introduction be hypothesized that the etiology of the disease is not the

F-w same in the 2 groups. For example, patients studied with
zL
Although genes have been convincingly shown to play L-dopa-responsive and L-dopa-resistant dystonia pre-
P-f
an important role in the etiology of schizophrenia, no sented many different features and were found to be eti-
0 _

genes with major effect have been identified.' The can- ologically different.'4 L-dopa-responsive dystonia is
44 didate gene association approach may help to identify caused by a mutation in the GTP-cyclohydrolase I gene
*
genes involved in schizophrenia even if they have only coding for a cofactor of tyrosine-hydroxylase, the rate-
_
a minor effect.2 limiting enzyme in dopamine biosynthesis. This example
An association between allele 2 of the 5HT2A receptor illustrates how classifying patients with dystonia accord-
gene and schizophrenia was identified in a Japanese ing to their response to L-dopa leads to an etiologically
population3 and subsequently replicated in a large mul- relevant classification of dystonia and to the identification
ticentre study4 and a family-based association study.5 of a causative gene (but not a gene involved in the metab-
Although other studies have failed to replicate this find- olism of the drug). A second example, more relevant to
ing,' a meta-analysis strongly supported the hypothe- complex disorders such as schizophrenia, is the
sis that the 5HT2A receptor gene is a minor susceptibili- apolipoprotein £4 allele in Alzheimer's disease. This allele
ty gene (odds ratio = 1.18) for schizophrenia.9 Further- has been identified as a risk factor in sporadic Alz-
more, because the risk allele 2 is the most frequent of the heimer's disease.'5 Patients carrying the apolipoprotein £4
2 alleles, the overall contribution of the 5HT2A receptor allele, particularly those who are homozygous, usually
gene to the risk of schizophrenia at the population level have a younger age at onset than noncarriers of allele s4.16
may be important (attributable fraction = 0.35). A sig- More recently, it has been reported that the genotypes in
nificant excess of allele 2 in patients with schizophrenia the apolipoprotein E locus influence the therapeutic
who are resistant to clozapine has also been reported in response to cholinomemetic drugs (see article on page 147
several studies"0," including a meta-analysis,'2 suggest- of this issue). Although the interplay between the
ing that this gene may modulate the therapeutic effect apolipoprotein £4 allele and therapeutic response to choli-
of clozapine. However, negative results have also been nomimetic drugs may be complex, this example again
reported.'3 illustrates how an association between a gene and
Traditionally, pharmacogenetics has investigated the response to drug therapy may reflect etiologic differences
effects of allelic variants of a gene, believed to influence between responders and nonresponders. It is therefore
the pharmacokinetics or pharmacodynamics of the drug, possible to use drug response to define relatively homo-
on the therapeutic efficacy of this drug. However, unless geneous subgroups of patients, which, in turn, may help
drug responders and nonresponders are comparable to identify the genes that increase the susceptibility to the
with respect to all other characteristics, it is not possible to disease in one or the other subgroups.
conclude unequivocally whether between-group differ- Several arguments support the hypothesis that patients
ences in allelic frequencies of the gene under investigation with schizophrenia who respond to conventional neu-
are entirely attributable to differences in drug responsive- roleptics and those who do not may represent different,
ness. Indeed, if in addition to differences in therapeutic though probably overlapping, phenotypes.'7"8 Responders
response, other differences (e.g., clinical, familial) are and nonresponders are characterized by several differ-
observed between responders and nonresponders, it may ences, including age at onset,'9 premorbid adjustment,'9

142 Revue pg...ik'etet de

Re.e de psychiatrie de neuroscience
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V61. X,T 02, 1999
Vol.
 T 02C polyorpism and izot

sex distribution,0 symptom profiles,2' family history,2 All patients with schizophrenia were interviewed
metabolic characteristics,3 brain metabolism2' and long- using the Diagnostic Interview for Genetic Studies
term outcome.25 Moreover, detectable differences in plas- (DIGS),3' and their medical records were reviewed by a
ma concentration26 or receptor occupancy" of neuroleptics research psychiatrist trained in the use of structured
have been found not to account for the variability in treat- interviews. Complementary information from the treat-
ment response. More recently, Meltzer et alP8 have shown ing physician and nurses were also obtained. Diagnosis
that response to clozapine is more likely in patients who was established on the basis of all the available informa-
have previously experienced a good response (and subse- tion. The severity of the disease at the time of the evalu-
quently became resistant) than in those who had a prima- ation was evaluated using the Brief Psychiatric Rating
ry resistance to conventional antipsychotic drugs. This and Scale (BPRS) global score,3" the Global Assessment Scale
othere' observations suggest that responders and nonre- (GAS) score, the percentage of time spent as an inpatient
sponders to clozapine may also be different with respect to and the score of responsiveness to neuroleptics.'7 The
the etiology of their disease-' overall pattern of severity of the disease was evaluated
It is therefore possible that the recruitment of schizo- using a 5-level ordinal scale included in the DIGS.?0 The
phrenic patients according to their long-term response control group consisted of 90 healthy volunteers who
to neuroleptics may help to identify genes involved in underwent a full psychiatric interview and were
the etiology of either of these putatively more homoge- screened for DSM-IV axis I disorders. All controls and
neous subphenotypes of schizophrenia. patients with schizophrenia were Caucasian, recruited
In this study, we compared allelic frequencies of the in Montreal and the Ottawa regions.
5HT2A receptor T102C polymorphism among 3 groups Written informed consent was obtained from all of
of subjects: 2 groups of patients with schizophrenia, the participants after the study had been thoroughly
classified according to a priori criteria into responders described to them.
and nonresponders to typical neuroleptics; and a group High-molecular-weight DNA was extracted from
of healthy volunteers. lymphocytes using standard techniques. Poly-
merase chain reation (PCR) amplification of a 342-bp
Methods fragment (nucleotides -24 to 318) was performed
using primers 5'TCTGCTACAAGTTCTGGCTT3' and
Patients with schizophrenia were recruited according to 5'CTGCAGCTTTTTCTCTAGGG3' according to a pro-
responsiveness to neuroleptic medication and long- tocol described by Warren et al.32 The PCR product was
term outcome. This study included 63 patients with digested with Hpa II. Allele 1(T102) corresponded to the
schizophrenia who did not respond to neuroleptics and nondigested fragment and allele 2 (102C) corresponded
39 who did. All nonresponders were diagnosed accord- to the digested product (216 and 126 bp fragments).
ing to DSM-IV criteria and were characterized by con- Gels were photographed and read blindly to the sta-
tinuous psychotic symptoms with no significant remis- tus of subjects.
sion within the past 2 years, at least 3 periods of treat- According to our predictions, we tested for associa-
ment with typical neuroleptics at optimal clinical tions between schizophrenia and allele 2 or genotype
requirements with no significant relief of symptoms in 2/2 using the X2 statistic, first in the group of patients
the preceding 5 years, and the inability to function with- with schizophrenia, and then in each subgroup of
out supervision in all or nearly all domains of social and patients and controls. Since we made 2 comparisons
vocational activities within the last 12 months. (responders and nonresponders v. controls and respon-
Neuroleptic-responders met DSM-IV criteria and had ders v. nonresponders), a Bonferroni correction was
at least 1 admission to a psychiatric care facility because applied (significance level was set at 0.05/3 = 0.016).
of an acute psychotic episode. They always experienced
full or partial remission in response to treatment with Results
typical neuroleptics and were able to function with only
occasional supervision in all or nearly all domains of The 2 groups of patients were comparable with respect to
social and vocational activities. They were required to age and sex. However, controls were significantly older,
be in remission or quasi-remission when compliant and more of them were women. The 2 groups of patients
with their medication. were very different with respect to clinical measures,

143

Vol. 24, no Z2, I1999

urS,I, I it Id
vb. 4%n6 "9 Jourzul
jo of PSV
umal .of too* & Murib4.wnft.
Psychiatry Neuroscience .. 143:j
Joober et al

reflecting the severity of the disease and the level of psy- allele 2 in nonresponders was higher than in respon-
chopathology at the time of the evaluation (Table 1). ders. No differences between neuroleptic-responders
Comparison of patients with schizophrenia (both and controls were observed (Table 2). The odds ratio

responders and nonresponders) with controls did not associated with genotype 2/2 in the group of neu-

show significant difference in allelic

frequencies, roleptic nonresponder patients was 2.06 (95% CI 1.84

though, as expected, allele 2 was more frequent in to 2.30) and the attributable fraction was 0.26. Patients

patients with schizophrenia. A comparison of geno- with genotype 2/2 were significantly younger at their

type 2/2 with genotypes 1/1 or 1/2 (recessive model) first contact with psychiatric care (19.4 ± 4.69 yr) than
showed a trend toward an excess of genotype 2/2 in patients with genotype 1/1 (23.7 ± 6.1 yr) (t =
2.64, df
the group of patients, but not in the controls (X2 =
3.23, =
54, p =
0.01). Patients with 1/2 genotype had an

df =
1, p =
0.07). When the 2 groups of patients were intermediate age at first contact with psychiatric care

analysed separately, a trend toward an excess of allele (21.1 ± 5.5 yr). When we analysed the data in men and
2 (X2 3.46, df
=
1, p = =
0.062) and a trend toward an women separately, a trend toward an excess in allele 2

excess of genotype 2/2 (x2 =4.69, df =

1, p =
0.030) were and in genotype 2/2 was observed in men (respective-
observed between neuroleptic-nonresponders and ly x2 = 4.53, p =
0.03; X2 =
5.53, p =
0.018) but not in

controls. Although nonsignificant, the frequency of women.

Table I: Demographic and clinical characteristics of patients and controls

Mean ± SD
Nonresponders Responders Controls
Characteristic n = 63* n = 39 n = 90

Mean age. yr 38.6 ± 6.9 41.8 ± 10.3 44.6 ± 12.8t

Men, % 74.4 71.7 52.81

French Canadian, % 47.4 58.9 55.4

Mean age at first contact, yr 18.1 ± 3.9 (55)1 24.2 ± 5.12 NA

Illness duration, yr 20.3 ± 7.0 (55) 17.9 ± 8.4 NA

Time as an inpatient, % 62 ± 38 (60)1 8.5 ± 12.4 NA

BPRS total score 49.0 ± 8.9 (534f 24.3 ± 3.8 NA

GAS score 29.9 ± 12.91 67.2 ± 9.3 90.9 ± 3.61

Neuroleptic response score 6.3 ± 0.74 (57)1 1.89 ± 0.68 NA

Pattern of severity 4.0 ± 0.49 (55)1 1.9 ± 0.84 NA

Note: BPRS = Brief Psychiatric Rating Scale; GAS = Global Assessment Scale
*Number in parentheses is the number of subjects, given when not equal to the whole sample size.
tYates correction was applied.
fp< 0.05. We used a I -way analysis of variance for quantitative variables and X- test for categorical variables.

Table 2: Analysis of genotypic (212 v. 1-2/1-1) and allelic (2 v. I) No.association

osfubjecwithts genotyp(%)e,Nonresponders~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~ ~of T102C polymorphism in SHT2A-receptor gene
~~~~~~.
No. of alleles, (%) Nonresponders
~and responders
and responders
Group I/I 1/2 2/2 v. controls* 1 ~~~2 v. controls*

All subjects
Controls 13 (14.4) 47 (52.2) 30 (34.4) 73 (40.5) 107 (59.5)
Responders 7 (17.9) 17 (43.6) 15 (38.5) XI= 0.32, P = 0.57 31 (39.7) 47 (60.2) x2 = 0.01, p =0.90

Nonresponders 7 (I1. 1) 24 (38.1) 32 (50.8) XI= 4.69, P = 0.030 38 (30.2) 88 (69.8) x2= 3.45, P = 0.06

Men

Controls 8 (19.0) 22 (52.4) 1 2(28.6) 38 (45.5) 46 (54.7)

Responders 4 (14.3) 1 2(42.8) 1 2(42.8) x2 = 1.52 P = 0.21 20 (35.7) 36 (64.9) xy =
1.25, P= 0.26
Nonresponders 6 (12.5) 1 6(34.0) 25 (53.2) x = 5.53, P = 0.018 28 (29.7) 66 (70.2) x2= 4.53, P = 0.03

Women

Controls 5 (10.4) 25 (52.1) 18 (37.5) 35 (36.4) 61 (63.5)

Responders 3 (27.3) 5 (45.5) 3 (27.3) x2 = 0.04, p =
0.84t1 11(50.0) 1 1(50.0) x2 = 1.37, p = 0.24

Nonresponders (6.2) 8 (50.0) 7 (43.7) X2= 0.3 1, P= 0.57 10 (31.2) 22 (68.75) x2=-0.28, P
=
0.59

:Idf=
tYates correction was applied.

144 Revue de
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Vol
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24, n0

gm i..-60 2, .119"..
2.
 TIO2 poymrphsm and sAcizophreiniaiit

Discussion to clozapinell' but not by studies using the BPRS,6'3

which focuses only on symptoms.31 The GAS assesses
We are using response to typical neuroleptic medication the overall severity of psychiatric disturbance, including
and long-term outcome to identify genetic factors the quality of social functioning.4 This overall severity is
involved in schizophrenia. Along this line, a trend toward influenced by the treatment but it is also correlated to
association between schizophrenia and allele 2 and geno- several other dimension of the disease (e.g., age at onset,
type 2/2 of the 5HTL-receptor gene was observed only in symptom profile, sex, premorbid level of functioning,
patients with schizophrenia who are resistant to typical neuropsychological performances). It is possible that
neuroleptics and have a poor long-term outcome. In con- improvement on GAS scores reflects not only sympto-
trast to 2 other studies,8"' this association was restricted to matic response to clozapine but also differences in the
men, and the age of onset was significantly younger in other dimensions, thus differences in the nature of the
patients with schizophrenia with genotype 2/2 than in disease. However, other studies found the 5-HT, recep-
those with 1/1 homozygous. This may suggest that resis- tor gene Hys452Tyr polymorphism (which is in com-
tance to neuroleptics or poor long-term outcome (often plete linkage disequilibrium with the T102C polymor-
observed in men with early age at onset) characterize the phism) to be associated with clozapine response in stud-
schizophrenia phenotype associated with allele 2 of the ies using the BPRS to assess the improvement of symp-
5HT,-receptor gene. If this is true, it may explain at least toms with clozapine treatment.33 It is therefore important
part of the discrepancies observed among the different to include in future studies separate measures of global
studies comparing patients with schizophrenia to normal severity of the disease and responsiveness to medication
controls with respect to 5HT2A receptor gene T102C allelic to disentangle the role of the 5-HTL receptor polymor-
distribution. Indeed, the power to detect an association phisms in these correlated but not identical dimensions.
between this polymorphism and schizophrenia depends Finally, some caution should be taken when inter-
on the proportion of severely affected, neuroleptic-resis- preting the results of this association study. First, popu-
tant patients, which may have varied from one study to lation-based association studies may lead to both false-
the other. positive and false-negative findings if the population is
An alternative interpretation to the "pharmacogenet- stratified. In spite of the fact that all patients in this
ics" hypothesis, postulating a specific association study were Caucasian, it is still possible that stratifica-
between allele 2 of the 5HT2A receptor and nonresponse tion occurred. However, no difference in allelic distrib-
to clozapine, is that this association is driven by the ution was identified among the major ethnic subgroup
severity or the long-term outcome, or both, which may (French Canadian) and the other ethnic subgroups.
differ between clozapine responders and nonrespon- Second, it is important to mention that this T102C poly-
ders. Indeed, if allele 2 of the 5HT2A receptor is associat- morphism is a silent polymorphism that does not result
ed with severe cases of schizophrenia, as suggested by in an amino-acid sequence change of the 5HT2A recep-
our results, it would be expected that patients with tor. It is therefore unlikely that this polymorphism is
schizophrenia refractory to all neuroleptics, including directly involved in increasing the genetic susceptibility
clozapine, would differ from responders to clozapine to schizophrenia. Potentially functional polymorphisms
with respect to the 5HT2A allele 2 frequency. In accor- in the 5HT2A receptor (such as the His452Tyr6'3335 in the
dance with this hypothesis, Arranz et all' identified an coding and -1438 G/A1l in the promotor regions) or in
association between 5HT2A receptor T102C and resis- other genes in strong linkage desequilibrium with the
tance to clozapine only when they used criteria that T102C polymorphism need to be investigated.
markedly differentiated clozapine responders and non- In conclusion, allele 2 of the 5HT2A receptor may be an
responders. When less stringent criteria were used, no etiological factor in schizophrenia, particularly in those
differences were found. Extreme response to clozapine forms that are severe and resistant to neuroleptics (both
was also the phenotype that was more clearly associated typical and atypical). Further investigation of the asso-
with the T102C polymorphism in the meta-analysis ciation between the 5HT2, gene and schizophrenia, with
study conducted by Arranz et al.12 It is also worth noting particular attention to neuroleptic response, overall dis-
that the positive associations between 5HT,A T102C ease severity and sex may help to confirm the role of
polymorphism and clozapine nonresponse were report- this gene in schizophrenia and to understand its puta-
ed by studies using the GAS to measure responsiveness tive genetic heterogeneity.

E.~~~~~~
Vol. 24, nno_:a:6-1,2,0r~
r7s1999 Journal of Psychiatry & Ne.irosdence 14$
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Wi5,;S-jEf
:Sw:tE
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146 Revue de psyci'atrie et de neuroscience Vol. 24, n0 2, 1999

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