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Analysis of the 5HT-2A T102C receptor polymorphism and psychotic symptoms in Alzheimer's disease.

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American Journal of Medical Genetics Part B (Neuropsychiatric Genetics) 144B:126 –128 (2007)
Brief Research Communication
Analysis of the 5HT-2A T102C Receptor Polymorphism and
Psychotic Symptoms in Alzheimer’s Disease
David Craig,* Caroline Donnelly, Dominic Hart, Robyn Carson, and Peter Passmore
Department of Geriatric Medicine, Division of Psychiatry and Neuroscience, Queen’s University, Belfast, Northern Ireland
Although the aetiology of psychotic symptoms in
Alzheimer’s disease (AD) is multi-factorial, alterations in serotonergic neurotransmission are
often implicated. Polymorphisms of the serotonin
receptor 5HT-2A are associated with hallucinatory symptoms and delusions in demented and
non-demented cohorts. This study examined the
role of the 5HT-2A T102C polymorphism in influencing psychotic symptoms in a large Northern
Ireland AD population (n ¼ 406, mean MMSE 13/
30). Forty-eight percent of patients experienced
delusional symptoms and 28% experienced hallucinations during the course of their dementia.
No significant association was found either in
frequency of genotype or allelic variation for
either set of symptoms. Furthermore, the mean
delusional and hallucinatory severity scores did
not differ significantly among the three genotype
groups. The lack of influence of the T102C polymorphism of the 5HT-2A receptor on the emergence of psychotic symptoms in AD contrasts with
previous reports in other cohorts involving smaller numbers of subjects. ß 2006 Wiley-Liss, Inc.
KEY WORDS: Alzheimer’s disease; polymorphism; psychosis; serotonin; 5HT-2A
Please cite this article as follows: Craig D, Donnelly C,
Hart D, Carson R, Passmore P. 2007. Analysis of the 5HT2A T102C Receptor Polymorphism and Psychotic Symptoms in Alzheimer’s Disease. Am J Med Genet Part B
144B:126–128.
INTRODUCTION
There is increasing interest in the role of genetic factors in
the causation of behavioral and psychological symptoms of
dementia (BPSD) also referred to as neuropsychiatric symptoms (NPS). These symptoms are diverse and unpredictable
but may originate from hitherto silent underlying inherited
risks emerging in the setting of neurodegeneration [Holmes,
2000].
Symptoms of a psychotic nature are common and associated
with significant carer burden [Donaldson et al., 1997, 1998].
Grant sponsor: Alzheimer’s Society Project; Grant sponsor:
Ulster Garden Villages research; Grant sponsor: British Geriatric
Society Start-up; Grant sponsor: NHS Research and Development
Office (NI) Bursary.
*Correspondence to: David Craig, Whitla Medical Building, 97
Lisburn Road, Belfast BT9 7BL, UK.
E-mail: david.craig@qub.ac.uk
Received 13 April 2006; Accepted 13 July 2006
DOI 10.1002/ajmg.b.30409
ß 2006 Wiley-Liss, Inc.
The aetiology of such symptoms is multi-factorial but alterations in serotonergic neurotransmission represent a common
biochemical correlate [Assal and Cummings, 2002; Ropacki
and Jeste, 2005]. Serotonergic receptor genotype–phenotype
interactions have been explored in non-demented populations
and investigators have attempted to examine their role in
Alzheimer’s disease (AD) in which a similar psychiatric
phenotype may emerge. In schizophrenic cohorts, the most
clearly linked serotonergic genotypic variant lies within the
serotonin 2A receptor (5-HT2A, HTR2A) gene, specifically the
T ! C 102 polymorphism [Williams et al., 1997; Prasad et al.,
2002].
There is a general lack of clarity regarding the influence of
serotonin-pathway polymorphisms in the causation of psychotic symptoms in AD. The 5-HT2A T102C polymorphism has
similarly generated the most interest although reports involving other serotonin pathway polymorphisms also exist
[Holmes et al., 1998; Nacmias et al., 2001; Sweet et al., 2001;
Rocchi et al., 2003; Assal et al., 2004]. Holmes et al. [1998] first
reported the influence of the C variant of the 5-HT2A T ! C 102
receptor polymorphism in producing hallucinatory symptomatology in AD—a finding subsequently confirmed in a study
involving a separate European cohort [Nacmias et al., 2001]. A
further positive report involving the 5-HT2A 102C variant and
psychotic symptoms [Rocchi et al., 2003] was followed by the
finding of a significant under representation of 5-HT2A 102C
homozygotes in a Chinese population of AD patients exhibiting
delusions [Lam et al., 2004]. Similarly, the 102T genotype of
the 5-HT2A receptor was weakly but significantly associated
with delusions in a recent report by Assal et al. [2004]. The 5HT2A receptor is a site of action for atypical antipsychotic
agents and there is some tentative evidence, in a small cohort,
that the T102C polymorphism negatively influences the efficacy of antipsychotic treatment in patients with probable AD
with BPSD who carry the C allele [Engelborghs et al., 2004].
In AD, both the T and the C allele at position 102 have
therefore been linked to psychotic symptoms and the C allele to
antipsychotic treatment response. Neither base change alters
the amino acid sequence of the 5HT-2A receptor as both
produce a serine amino acid at codon 34 [Warren et al., 1993].
The change may, however, have functional consequences both
in terms of unconfirmed reports of lower reported cortical
receptor density in C allele schizophrenic patients identified
post-mortem [Polesskaya and Sokolov, 2002; Bray et al., 2004]
and higher recorded N100 amplitudes in CC homozygotes after
clozapine treatment [Yu et al., 2001]. This may reflect the
influence of a separate gene existing in linkage disequilibrium.
The uncertain of role of the T102C 5-HT2A polymorphism
in influencing psychotic symptoms in AD encouraged us to
examine its carriage in a large, well characterized cohort which
exists within the genetically homogeneous Northern Ireland
population.
METHODS
Following ethical approval from the Research Ethics
Committee, The Queen’s University of Belfast, informed
5HT-2A Polymorphism and Psychosis in AD
written consent was obtained from next-of-kin and patients
where possible. Patients, fulfilling the criteria for probable AD
[McKhann et al., 1984], were identified from out-patient
memory clinic records based at three centers (Belfast City
Hospital Trust, Mater Infirmorum, and Holywell Hospital).
Patients were included who had a carer with contact at least
3 days a week for at least 3 years to ensure reliability of data. A
validated neuropsychological assessment tool, the Neuropsychiatric Inventory with Caregiver Distress (NPI-D) [Kaufer
et al., 1998] was employed to record delusional and hallucinatory symptomatology and carers were asked regarding known
prior psychiatric history affecting the subjects. Carers are
permitted in the NPI-D to provide overall symptom score
according to the composite of frequency x severity.
DNA extracted from peripheral blood leukocytes was
analyzed for the 5HT-2A T102C polymorphism as previously
reported [Holmes et al., 1998]. Chi-squared analysis was used
to compare genotype and allele frequencies and to test whether
the genotype frequencies deviated from expected Hardy–
Weinberg equilibrium. Age and MMSE were compared using
the Mann–Whitney test and a one-way analysis of variance
(ANOVA) was employed for psychotic symptom score. The level
of statistical significance was set at less than 5%. Data were
analyzed using the SPSS computer software program [Chicago
Ill, 2000].
RESULTS
Genotyping was performed in 406 patients. The mean
MMSE was 13/30. Thirty-one percent were male. The average
age of the cohort was 78. There was no difference in age or
MMSE scores between patients in the three genotype groups
CC, TC, and TT. Alleles did not differ significantly from that
predicted by the Hardy–Weinberg equilibrium. Table I provides frequency data for the 5HT-2A T102C polymorphism in
those with and without delusional symptoms. Approximately
half (48%) of subjects experienced this symptom during the
course of their dementia.
A chi-square analysis failed to show any significant alteration in the distribution of CC, TC, TT genotypes between
groups. Allelic carriage was similarly non-significant (T allele:
delusions absent 45.9%, delusions present 40.8%, ChiSquare ¼ 2.110, df ¼ 1, P ¼ 0.146). ANOVA analysis of severity
data in 188 delusional patients failed to reveal any significant
relationship between symptom severity score and genotype
(P ¼ 0.10; mean score CC-6/12, TC-7/12, and TT-5/12).
Table II shows the proportions of patients experiencing
hallucinations according to T102C genotype. Hallucinations
were present in 28% of those surveyed. No significant relationship was seen either in frequency of genotype (above) or a
separate analysis of allelic variation (T allele: hallucinations
absent 43.7%, hallucinations present 41.0% Chi-Square ¼
0.200, df ¼ 1, P ¼ 0.654). Mean hallucination severity scores
in 108 patients according to genotype were as follows: CC-5/12,
TC-4/12, and TT-4/12. These differences were not significantly
different (ANOVA, P ¼ 0.45).
After subjects with a positive prior psychiatric history were
removed from the genotypic analysis, the values of chi-square
remained statistically insignificant (delusions, Pearson ChiTABLE I. Analysis of Delusions According to Genotype of
5HT-2A T102C Polymorphism
CC
TC
127
TABLE II. Analysis of Hallucinations According to Genotype of
5HT-2A T102C Polymorphism
Hallucinations
Absent
Present
CC
TC
TT
98 (33.3%)
33 (29.5%)
135 (45.9%)
64 (57.1%)
61 (20.7%)
15 (13.4%)
Pearson Chi-Square ¼ 4.805, df ¼ 2, P ¼ 0.090.
Square ¼ 1.673, df ¼ 2, P ¼ 0.433; hallucinations, Pearson ChiSquare ¼ 4.975, df ¼ 2, P ¼ 0.083).
DISCUSSION
As previously reported, delusional symptoms were seen to
affect around half of subjects and in over a quarter of patients
hallucinations were experienced [Craig et al., 2005]. Genotyping indicated that the T102C polymorphism of the serotonin 2A
receptor exerts no influence on the emergence of delusional/
hallucinatory symptoms in AD. There is some indication of a
trend effect involving hallucinations and the T allele which
appears to be underrepresented in those with this symptom but
this was not confirmed in a separate analysis of allele carriage.
The site of the receptor, 13q14-q21, has not been, as far as we
are aware, identified in linkage studies as one of potential
interest in the search for loci relevant to psychotic change in
AD [Bacanu et al., 2002].
Differences in populations under study and their size and
methodologies employed may account for the differences in
reported results. The previous findings of a positive association
between T102C and psychosis in AD utilizing the NPI have
been based on studies involving smaller cohorts [Assal et al.,
2004; Lam et al., 2004]. The population presented herein is of a
sufficiently advanced phase of illness (mean MMSE 13/30) that
adequate time has passed to allow the phenotype to emerge—
psychotic phenomenon typically appear in the early phase of
disease [Devanand et al., 1997; Haupt et al., 2000]. The work is
limited by its cross-sectional nature and dependent on the
recall of a carer (albeit one with an intimate knowledge of the
patient’s activities).
Psychosis in the context of dementia is a complex syndrome
in which many different genetic and environmental factors
operate—the lack of clear data supporting a consistent
contribution by the 5HT-2A receptor polymorphism suggests
its influence is minor overall while questions remain regarding
the functional significance of this particular SNP and the effect
of allelic variation on, for example, the expression of transcribed mRNA sequence in brain post-morten studies [Polesskaya and Sokolov, 2002; Bray et al., 2004].
Future studies may seek to examine longitudinally the
appearance and disappearance of these symptoms as well as
the pharmacogenomic aspects of 5HT-2A variation and its
influence of drug efficacy particularly with regard to antipsychotic response in AD.
ACKNOWLEDGMENTS
This work was supported by an Alzheimer’s Society Project
Grant, an Ulster Garden Villages research grant and a British
Geriatric Society Start-up grant. CD is supported by a NHS
Research and Development Office (NI) Bursary.
TT
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Absent
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