No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients

Psychiatry Research 105 Ž2001. 175᎐185

No association between T102C polymorphism of serotonin-2A receptor gene and clinical phenotypes of Chinese schizophrenic patients Ronald Yuk Lun Chena,U , Pak Shamb, Eric Yu Hai Chena , Tao Li b, Eric Fuk Chi Cheung a , Tomy Chok King Hui a , Carol Lan Kwok a , Felice Lieh-Mak a , Jing Hua Zhao b, David Collier b, Robin Murray b a

Department of Psychiatry, Uni¨ ersity of Hong Kong, Hong Kong SAR, PR China b Department of Psychiatry, Institute of Psychiatry, London, UK

Received 20 July 2001; received in revised form 1 October 2001; accepted 2 October 2001

Abstract Serotonin dysfunction has been implicated in the pathogenesis of schizophrenia. Previous studies have shown an association between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia. However, negative findings have also been reported. One possible explanation for such discrepancy is disease heterogeneity due to the current limitations in the diagnosis of schizophrenia. We conducted a case᎐control study of the T102C polymorphism with detailed characterisation of the clinical phenotypes to investigate the possible association with schizophrenia not only at the diagnostic level, but also with reference to other clinical phenotypes potentially related to serotonin dysfunction. Four hundred and seventy-one biologically unrelated schizophrenic patients and 523 unrelated healthy controls of Han Chinese descent in Hong Kong were compared for genotypes and allele frequencies of the T102C polymorphism by PCR amplification and restriction analysis. No evidence of association was detected at the diagnostic level and various clinical phenotypes. However, we found a trend association with small effect size between genotype 102Tr102C and patients with better verbal fluency and less motor co-ordination soft neurological signs. There is a need for future large-scale studies on the possible associations between genetic polymorphisms and neurocognitive function impairments in schizophrenia. 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Genetics; Neurocognitive deficit; Frontal lobe dysfunction

U

Corresponding author. Department of Psychiatry, Room 219, J2 Block, Queen Mary Hospital, Pokfulam, Hong Kong, PR China. Tel.: q852-28553057; fax: q852-28551345. E-mail address: [email protected] ŽR. Yuk Lun Chen.. 0165-1781r01r$ - see front matter 䊚 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 5 - 1 7 8 1 Ž 0 1 . 0 0 3 4 3 - 2

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1. Introduction Schizophrenia is a major psychiatric illness affecting approximately 1% of the world population. The clinical features include positive Žhallucination, delusion and thought disorder. and negative symptoms Žapathy, affective flattening, poverty of speech and social withdrawal.. Impairment of neurocognitive function, especially attention, memory and frontal lobe function, is also noted. Existing research findings have supported the hypothesis that schizophrenia is an inherited disorder ŽKendler and Diehl, 1993; McGuffin et al., 1995., although environmental factors are also relevant. Current evidence supports an oligogenic or polygenic model with multiple susceptibility genes, each with small effect size, rather than monogenic aetiology. Recently, the serotonin system has been implicated in the pathogenesis of schizophrenia. 5HT2a receptor density was found to be significantly reduced in post-mortem brains of schizophrenic patients without prior drug treatment ŽMita et al., 1986.. Clozapine is the prototype of atypical antipsychotics which has strong antagonism to the 5HT2a receptor. Approximately 50% of treatment-resistant schizophrenic patients respond to clozapine, with significant improvement in negative symptoms ŽMeltzer et al., 1991; Meltzer, 1992. and in cognitive functions including attention and verbal fluency ŽGoldberg and Weinberger, 1994; Lee et al., 1994.. Moreover, serotonin dysfunction has been implicated in the pathogenesis of impulsive behaviour, e.g. violence and suicide. There is a consistent association between low concentrations of CSF 5-HIAA and suicidal behaviour ˚ ŽAsberg, 1997.. This association is not restricted to depressive disorder but also present in schizophrenia. A significant proportion of schizophrenic patients exhibit suicidal behaviour. This subgroup of patients may have an underlying genetic predisposition to suicidal tendency. The human 5HT2a receptor gene is located on chromosome 13q14-q21 ŽHsieh et al., 1990; Chen et al., 1992.. Recently, a significant association between a silent mutation ŽT102C. in the 5HT2a receptor gene and schizophrenia was found in a

sample of Japanese patients and unrelated healthy controls ŽInayama et al., 1994.. This has been subsequently confirmed by a European multicenter association study of schizophrenia ŽWilliams et al., 1996. and other association studies ŽErdmann et al., 1996; Spurlock et al., 1998.. These studies found that the 102C allele frequency was significantly higher in schizophrenic patients than in controls. However, Tay and coworkers revealed a predominance of the 102T allele am ong Singapore Chinese m ale schizophrenic patients ŽTay et al., 1997.. These initial positive findings were challenged by subsequent studies which failed to replicate such an association ŽArranz et al., 1995; Malhotra et al., 1996; Nimgaonkar et al., 1996; Chen et al., 1997; Hawi et al., 1997; Verga et al., 1997; Shinkai et al., 1998; He et al., 1999; Lin et al., 1999.. There are two possible explanations for these inconsistent findings. It is possible that the positive results were due to artefacts such as population stratification and inadequately matched controls. Alternatively, there may be genetic heterogeneity between the patient samples such that an association is present in some, but not others. The current diagnosis of schizophrenia is based on a broad syndromal classification with much clinical heterogeneity. Different clinical subgroups of schizophrenic patients may have different profiles of aetiological factors. Most of the previous studies have focused only on a broad diagnosis of schizophrenia without detailed examination of clinical manifestations and the associated biological traits. In view of these difficulties, it is important to conduct case᎐control studies with detailed characterisation of the various phenotypes of the schizophrenic illness from a homogenous ethnic population. In this study, we compared the genotype distributions and allele frequencies of the T102C polymorphism of the 5HT2a receptor gene between schizophrenic patients and unrelated healthy controls of Han Chinese descent in Hong Kong. The patient sample was further characterised for certain clinical and neuropsychological features that might be potentially related to serotonin dysfunction.

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2. Methods

2.2. Assessment of clinical profiles

2.1. Subjects

The patients were classified into the subtype diagnoses of paranoid and non-paranoid which included disorganised, catatonic, residual and undifferentiated types. Nine patterns of longitudinal course of illness were identified retrospectively by case note review. They included: Ža. episodic with inter-episodic residual symptoms and prominent negative symptoms; Žb. episodic with inter-episodic residual symptoms; Žc. episodic with no inter-episodic residual symptoms; Žd. continuous with prominent negative symptoms; Že. continuous; Žf. single episode, in partial remission, with prominent negative symptoms; Žg. single episode, in partial symptoms remission; Žh. single episode in full remission; and Ži. other or unspecified pattern. They were further combined into three categories of episodic Ža, b and c., continuous Žd and e. and single episode Žf, g and h.. Those patients who had other or unspecified patterns Ži. were excluded from statistical analysis. Both subtypes of diagnoses and course patterns were evaluated according to the criteria of DSM-IV ŽAmerican Psychiatry Association, 1994.. The Positive and Negative Syndrome Scale ŽKay et al., 1987. was used to assess the clinical symptoms of patients. It consisted of positive symptom, negative symptom, general symptom and aggression risk subscales. The onset age of individual patients was determined as the age when psychotic symptoms were first presented or of first contact with psychiatrist. This information was collected from medical records and supplemented by information from patients and their family members. Absence or presence of a history of suicidal behaviour was recorded. History of violence was rated on a three-point scale. ŽNo. indicated no physical violence and no significant verbal aggression, Žmild. referred to patients with significant and frequent verbal aggression or violence to object or mild physical aggression to person, and Žsevere. represented patients with physical violence to person resulting in medical consultation of the victims. Absence or presence of a family history of mental illness was evaluated from med-

Four hundred and seventy-one biologically unrelated Han Chinese patients Ž334 males and 137 females. aged 18᎐60 Žmean age s 42.3; S.D.s 10.28. meeting DSM-IV diagnostic criteria for schizophrenia ŽAmerican Psychiatry Association, 1994. were recruited from the Department of Psychiatry, Queen Mary Hospital and Castle Peak Hospital, Hong Kong. Diagnosis of the patients was ascertained by using the Structured Clinical Interview for DSM-IV ŽSCID. ŽFirst et al., 1998b.. Patients were carefully screened and those with a history of substance abuse, mental retardation, neurological disorder, major medical illness that could affect brain functioning, head injury with loss of consciousness and a history of having received electroconvulsive therapy within the past 2 years were excluded. Five hundred and twenty-three biologically unrelated healthy volunteers Ž308 males and 215 females. were recruited from blood donors Ž n s 457. and other sources Ž n s 66. including people from the general public, hospital staff, and medical and nursing students Žmean age s 41.9; S.D.s 9.79.. The blood donors could not be personally interviewed because of the Hong Kong Red Cross Policy. However, each potential blood donor in Hong Kong would be excluded if he or she was under a doctor’s care, taking any prescribed medication at the time of donation and suffering from any significant illness. The other 66 healthy volunteers were screened for the presence of psychiatric illness by using the Structured Clinical Interview for DSM-IV ŽSCID. non-patient version ŽFirst et al., 1998a.. Those with psychiatric illness, significant medical illness and family history of psychosis were excluded. All subjects were of Han Chinese descent. Patients and controls were not significantly different for age Žt s 0.66; Ps 0.509.. There was a higher proportion of females in controls Ž41.1%. than patients Ž29.1%. Ž ␹ 2 s 15.66, d.f.s 1, and P- 0.001.. Written informed consent was obtained from all the participants who were interviewed.

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ical records and supplemented by information from patients and their family members. Response to treatment was evaluated retrospectively over the course of an individual patient’s illness and was rated on a three-point scale. Good response referred to complete symptom remission and return to the level of premorbid functioning. Negligible response indicated persistent symptoms for more than 2 years despite optimal dosage of at least two different anti-psychotic drugs for 6 weeks each. Patients with treatment outcome between good and poor response were considered as partial response. All of the 471 patients were interviewed. The diagnostic subtypes and PANSS rating were completed for all patients. However, the onset age of four patients, course patterns of 32 patients, family history of mental illness of five patients, history of suicidal behaviour of four patients and violence of two patients could not be determined because the information was not documented in medical records, and the patients or their family members could not provide accurate information. The treatment response for 31 patients could not be assigned on the three-point scale because their duration of illness was less than 2 years. 2.3. Neurocogniti¨ e assessment A semantic verbal fluency test was conducted for the ‘animal’ category. Each patient was asked to generate as many exemplars in the animal category as possible in 1 min. The word output was taped for later analysis. The motor co-ordination soft neurological signs examination extracted from the Cambridge Neurological Inventory ŽChen et al., 1995. was administrated. It consisted of finger thumb opposition, finger thumb tapping, disdiadochokinesia, fist᎐edge-palm test and Ozeretski test. The Stroop test was conducted according to standard procedures ŽPerret, 1974.. Briefly, each patient was requested to perform two tasks. The first ‘colour task’ required the patient to read the words of colour names, which was printed in colours different from the meaning of the words. The second ‘colour-word task’ required the patient to read the printed colour of the words. Two minutes were allowed for each

task. The numbers of correct and incorrect responses were recorded. The colour score and colour᎐word score was calculated from the number of correct responses minus incorrect responses in the colour task and the colour᎐word task, respectively. The general cognitive function of the patients was evaluated by the information subscale of the Wechsler Adult Intelligence Scale ŽThe Hong Kong Psychological Society, 1989.. There were 6, 18, 19, 62 and 87 patients who refused to be examined for intelligence, verbal fluency, soft signs, Stroop colour task and Stroop colour word task, respectively. 2.4. Genotyping Venous blood samples, anticoagulated with EDTA, were collected from all participants with informed consent. Genomic DNA extraction was performed by standard procedures. The T102C polymorphism was detected using the oligonucleotide primers 5⬘-TCTGCTACAAGTTCTGGCTT-3⬘ and 5⬘-CTGCAGCTTTTTCTC TAGGG-3⬘ modified from the procedure of Warren et al. Ž1993.. Briefly, the PCR amplification was performed by using 0.1-␮g genomic DNA, 0.1 ␮M of each primer and 1.5 mM MgCl 2 in a final volume of 50 ␮l. The sample was subjected to three cycles of 3 min at 94 ⬚C, 45 s at 60 ⬚C, 1.5 min at 72 ⬚C, then 35 cycles of 1 min duration at 94 ⬚C, 45 s at 60 ⬚C, 1.5 min at 72 ⬚C, and finally 72 ⬚C for 10 min. The PCR product Ž342 bp. was digested using the enzyme MspI ŽNew England Biolab, cat. no. 106S.. The 102T allele gives fragments of 342 bp, while the 102C allele gives fragments of 126 and 216 bp, respectively. DNA products were electrophoresed in 2% agarose gel, followed by ethidium bromide staining. The raters who determined the genotypes and those who performed clinical assessments were blinded to the results from each other. All the patients and controls who participated in this study were genotyped. 2.5. Statistical analysis The genotype distributions of the T102C polymorphism of the 5HT2a receptor gene in patients

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and controls were evaluated for deviation from the Hardy᎐Weinberg equilibrium using the ␹ 2 test. Comparison between the patients and controls for the difference of genotype distributions, allele frequencies and homozygosity was analysed by the ␹ 2 test. Further comparison of clinical profiles among the schizophrenic patients with different genotypes was carried out by analysis of variance for continuous variables or the ␹ 2 test for categorical variables. Similarly, the neurocognitive function among patients with various genotypes was compared by using analysis of covariance controlled for age. All the statistical tests were two-tailed with the significance level set at P- 0.002 after the Bonferroni correction for 23 statistical comparisons. When the difference of allele frequency between patients and controls was considered as the primary analysis of our study and the type I error set conventionally at 0.05, our current sample size with statistical power of 0.80 could detect an odds ratio of 1.44 or above.

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cies of the T102C polymorphism of the 5HT2a receptor gene among Han Chinese schizophrenic patients and unrelated healthy controls are shown in Table 1. The genotype frequencies do not significantly deviate from the Hardy᎐Weinberg equilibrium in patients Ž ␹ 2 s 0.126, d.f.s 1, Ps 0.723. and controls Ž ␹ 2 s 0.594, d.f.s 1, Ps 0.441.. There are no significant difference in genotype distributions or allele frequencies between patients and controls. Similarly, no significant difference was noted when male and female participants were analysed separately. No excess of homozygosity was found between patients and controls Ž ␹ 2 s 0.26, d.f.s 1, Ps 0.613.. 3.2. Clinical profiles The associations between the clinical profiles of schizophrenic patients and their genotype distributions are shown in Table 2. No significant association was found between the clinical profiles and the genotype distribution.

3. Results 3.3. Neurocogniti¨ e dysfunction 3.1. Intergroup comparison The genotype distributions and allele frequen-

Table 3 shows the comparison of neurocognitive performance among patients with various

Table 1 Genotype distributions and allele frequencies of the T102C polymorphism of the 5HT2a receptor gene among schizophrenic patients and healthy controls Genotypesa

Allele frequencyb

102Tr102T

102Tr102C

102Cr102C

102T

102C

Patients Ž n s 471. Male Ž n s 334. Female Ž n s 137.

209 Ž0.44. 146 Ž0.44. 63 Ž0.46.

212 Ž0.45. 148 Ž0.44. 64 Ž0.47.

50 Ž0.11. 40 Ž0.12. 10 Ž0.07.

630 Ž0.67. 440 Ž0.66. 190 Ž0.69.

312 Ž0.33. 228 Ž0.34. 84 Ž0.31.

Controls Ž n s 523. Male Ž n s 308. Female Ž n s 215.

234 Ž0.45. 140 Ž0.46. 94 Ž0.44.

226 Ž0.43. 133 Ž0.43. 93 Ž0.43.

63 Ž0.12. 35 Ž0.11. 28 Ž0.13.

694 Ž0.66. 413 Ž0.67. 281 Ž0.65.

352 Ž0.34. 203 Ž0.33. 149 Ž0.35.

a

All subjects: ␹ 2 s 0.635, d.f.s 2, Ps 0.728; and Cramer’s ␾ s 0.02. Male: ␹ 2 s 0.207; d.f.s 2; Ps 0.902. Female: ␹ 2 s 2.860; d.f.s 2; P s 0.239. b All subjects: odds ratio s 1.02 Ž95% CI, 0.85᎐1.24., ␹ 2 s 0.04, d.f.s 1, Ps 0.839; and ␾ s 0.004. Male: odds ratio s 0.95 Ž95% CI, 0.75᎐1.20.; ␹ 2 s 0.15, d.f.s 1, and Ps 0.699. Female: odds ratio s 1.20 Ž95% CI, 0.86᎐1.68.; ␹ 2 s 1.03, d.f.s 1, P s 0.310.

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Table 2 The genotype distributions in association with clinical profiles among schizophrenic patients Genotypesa 102Tr102T

102Tr102C

102Cr102C

Diagnosis Paranoid Non-paranoid

170 39

164 48

42 8

Course pattern Episodic Continuous Single episode

122 49 17

135 43 12

29 14 3

Suicide Absence Presence

148 60

139 70

27 23

Violence No Mild Severe

97 59 53

96 67 47

17 9 24

Treatment response Full Partial Negligible

30 78 86

18 82 98

5 18 25

159 48

159 50

41 9

Family history of mental illness Absence Presence Onset age, mean (S.D.)d Years

Nc s 207 25.35 Ž9.08.

PANSSb , mean (S.D.) Positive symptoms Negative symptoms General symptoms Aggression risk Total scores

N s 209 13.77 Ž6.51. 21.25 Ž8.80. 31.19 Ž8.82. 4.12 Ž1.95. 70.33 Ž20.42.

N s 211 24.36 Ž7.82. N s 212 14.95 Ž7.07. 22.14 Ž8.20. 32.21 Ž9.60. 4.33 Ž2.44. 73.64 Ž22.19.

N s 49 22.37 Ž6.82. N s 50 14.20 Ž7.90. 20.36 Ž9.33. 31.28 Ž11.71. 4.28 Ž3.15. 70.12 Ž28.52.

a

No statistically significant difference was noted among the three genotypes by using ␹ 2 and ANOVA test for categorical and continuous variables, respectively. b PANSSs Positive and Negative Syndrome Scale. c N s number of subjects. d S.D.s standard deviation.

genotypes. All the neurocognitive functions were controlled for age. There were trends of better verbal fluency performance and less motor coordination soft neurological signs in patients with genotype 102Tr102C with effect sizes of 0.023 and 0.024, respectively.

4. Discussion In this study, we could not confirm the previous finding of an association between the T102C polymorphism of the 5HT2a gene and schizophrenia at the diagnostic level ŽErdmann et al., 1996;

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Table 3 Neurocognitive function of schizophrenic patients in association with their genotypes

Verbal fluency Mean correct items Mean incorrect items

Soft signs Mean score

Stroop test Mean colour score Mean colour word score

102Tr102T

102Tr102C

102Cr102C

Nb s 199 12.86 Ž5.79.

N s 205 14.43 Ž5.74.

N s 49 12.16 Ž5.41.

0.11 Ž0.62.

0.13 Ž0.72.

0.08 Ž0.40.

N s 201 4.12 Ž3.97.

N s 204 2.92 Ž3.18.

N s 47 3.28 Ž3.43.

N s 177 107.69 Ž9.89. N s 166 60.70 Ž24.88.

N s 193 107.55 Ž11.40. N s 181 62.13 Ž22.70.

N s 39 110.67 Ž5.46. N s 37 59.24 Ž24.28.

Statistics a

Effect size Ž ␩2 .

Observed power

F s 5.381 Ps 0.005 F s 0.155 Ps 0.856

0.023

0.479

0.001

0.005

F s 5.486 Ps 0.004

0.024

0.492

F s 1.415 Ps 0.244 F s 0.282 Ps 0.755

0.007

0.057

0.001

0.008

a

ANCOVA controlled for age. N s number of subjects; standard deviation ŽS.D.. parentheses.

b

Inayama et al., 1996; Williams et al., 1996; Tay et al., 1997; Spurlock et al., 1998.. Our data are in line with other negative association studies ŽArranz et al., 1995; Malhotra et al., 1996; Nimgaonkar et al., 1996; Chen et al., 1997; Hawi et al., 1997; Verga et al., 1997; Shinkai et al., 1998; He et al., 1999; Lin et al., 1999. and negative linkage studies ŽBarr et al., 1994; Coon et al., 1994; Karayiorgou et al., 1994. on this polymorphism. The 102C allele was found to be associated with schizophrenia in the European multicentre association study of schizophrenia ŽWilliams et al., 1996.. The odds ratios for the seven samples ranged from 0.90 to 1.55. However, the overall association was mainly accounted for by the French sample Žodds ratio s 1.55; 95% CI s 1.05᎐2.29.. The statistical power of our study is able to detect an odds ratio of such magnitude. There are several possible explanations for the discrepancy of results regarding the association between the T102C polymorphism of the 5HT2a gene and schizophrenia. First, it may be due to chance positive findings. However, it may be too early to attribute all those previous studies with

positive results across various ethnic populations to chance findings alone. A second possibility is that differences across studies may be due to genetic heterogeneity. In this case, the association of the polymorphism with schizophrenia may be present only in certain ethnicities. It is important to note that the allele 102C is not consistently found to be associated with schizophrenia even among the studies with positive results. It was also reported that the allele 102T was associated with Singapore Chinese male schizophrenic patients ŽTay et al., 1997.. Moreover, the allele frequencies among the Chinese population in our study and other studies ŽChen et al., 1997; Tay et al., 1997; Lin et al., 1999. show a predominance of 102T rather than 102C, as reported in several European populations ŽWilliams et al., 1996.. Different allele frequencies among different ethnic populations may contribute to inconsistent results from case᎐control association studies. A third possible explanation is that differences between studies may be the result of disease heterogeneity of the patient samples in different studies. Different studies may have different mixes

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of subtypes of schizophrenic patients that can be revealed by detailed characterisation of clinical features of the patients. In our study, no significant association was detected between the polymorphism and the clinical variables, which is consistent with other studies concerning clinical symptoms ŽIshigaki et al., 1996; Shinkai et al., 1998; Serretti et al., 2000.. Concerning the treatment response, allele 102C might be associated with patients characterised by poor response to anti-psychotics and poor longterm outcome ŽJoober et al., 1999.. The genotype distribution in our study did not differ among the three types of treatment response, namely full, partial and negligible. When only those patients with negligible treatment response were compared with healthy controls, no difference in genotype or allelic distribution was noted. This is consistent with the finding from Nimgaonkar and co-workers who used similar rating criteria for treatment response ŽNimgaonkar et al., 1996.. Nevertheless, it has to be emphasised that assessing pharmacotherapeutic response based on retrospective qualitative evaluation is not the best method. Further, a large-scale association study specifically designed for the prospective evaluation of treatment response in the Han Chinese population is needed to resolve this issue. Neurocognitive impairment, especially frontal lobe dysfunction, is common in schizophrenia. Support for its familial nature was provided by studies showing that healthy first degree relatives of schizophrenic probands also had similar, but less severe neurocognitive dysfunction to that in their schizophrenic relatives ŽHarvey et al., 1981; Erlenmeyer Kimling et al., 1989; Pogue-Geile et al., 1989, 1991; Condray et al., 1992; Cannon et al., 1994; Keefe et al., 1994; Chen et al., 2000a,b.. The verbal fluency task requires subjects to initiate a self-directed search in their inner lexicon to retrieve the appropriate words. It has been found to involve the fronto-temporal region in neuroimaging studies ŽFrith et al., 1991.. Motor coordination soft signs primarily reflect a disturbance of motor sequencing, which has been attributed to abnormalities in the fronto-subcortical circuit ŽFlashman et al., 1996., basal ganglia

ŽSchroder et al., 1991., and sensorimotor and ¨ supplementary motor cortex ŽSchroder et al., ¨ 1995.. We found a trend toward better verbal fluency performance and less motor co-ordination soft signs in patients with genotypes 102Tr102C. However, the contribution to neurocognitive function from this genotype is very small in view of their small effect sizes. Other neurotransmitter systems and their genetic compositions may also play a significant role in neurocognitive function. It has been suggested that dopamine has an essential neuromodulatory effect on the signal-tonoise ratio in frontal cognitive tasks ŽDaniel et al., 1989, 1991; Mattay et al., 1996.. The role of serotonin in frontal lobe function may be related to the inhibitory effect of the serotonin system on the dopamine system at the origin in the mid-brain and at the terminal dopaminergic field in the forebrain in schizophrenic patients ŽKapur and Remington, 1996.. Evidence from animal studies showed that clozapine or other specific 5HT2 antagonists Že.g. ritanserin . can increase dopamine activity in prefrontal cortex ŽSvensson et al., 1995.. Further large scale studies that characterise neurocognitive function and analyse the genetic interaction of other relevant neurotransmitter systems, e.g. serotonin and dopamine, are necessary. In conclusion, no significant association was found between the T102C polymorphism of the 5HT2a receptor gene and schizophrenia at the level of diagnosis and clinical phenotypes in Han Chinese. However, there was a trend towards a small degree of association between genotypes 102Tr102C and better frontal lobe function regarding verbal fluency performance and motor co-ordination. The discrepancy of these results from previous studies with positive findings may be due to ethnic differences or different mixes of patient samples in different studies. In view of the uncertainties in the broad clinical diagnosis of schizophrenia, detailed characterisation of biological phenotypes is essential to reveal the genetic predisposition for this disease. Frontal lobe function as an inherited trait may serve as a good candidate phenotype for future association or linkage studies on schizophrenia.

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