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Keywords:

  • case-control;
  • association;
  • schizophrenia;
  • COMT;
  • negative symptom

Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The gene encoding Catechol-O-methyltransferase (COMT), a dopamine catabolic enzyme, has been associated inconsistently with schizophrenia in spite of consistent evidence for dopaminergic dysfunction in the prefrontal cortex (PFC) of schizophrenia. Since one contribution to this inconsistency might be genetic heterogeneity, this study investigated whether the COMT gene was associated with the development and symptoms of schizophrenia in relatively genetically homogeneous Chinese schizophrenic patients. We analyzed two polymorphisms (rs740603 and rs4818) of the COMT gene in a case-control study of 604 Han Chinese (284 patients and 320 controls). The patients' psychopathology was assessed using the Positive and Negative Syndrome Scale (PANSS). We found no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups. Quantitative trait analysis by the UNPHASED program showed that the rs740603 and rs740603(G)-rs4818(G) haplotypes were associated with negative symptoms in the schizophrenic patients, particularly among female patients. Thus, the COMT gene polymorphisms may not contribute to the susceptibility to schizophrenia, but may contribute to the negative symptoms of schizophrenia among Han Chinese. © 2012 Wiley Periodicals, Inc.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

The Catechol-O-methyltransferase (COMT) gene has been studied widely among schizophrenics, using both case-control and family designs [Sagud et al., 2010]. Moreover, the COMT gene lies on chromosome 22q11.1–q11.2, a region which is significantly associated with schizophrenia in several linkage studies [Pulver et al., 1994; Owen, 2005]. The COMT Val158/108Met (rs4680) polymorphism is the gene variant studied most widely in psychiatry, because of its functional relevance [Okochi et al., 2009]. However, current data on other variants of the COMT gene could also be relevant [Shield et al., 2004; Molero et al., 2007]. Several other SNPs that were tested for an association with schizophrenia have shown conflicting results [Chen et al., 2004; Handoko et al., 2005]. A recent study analyzing 14 polymorphisms in a case-control study of 876 Han Chinese found that none of these polymorphisms contributed to the risk of developing schizophrenia or its subtypes, as assessed using allele/genotype and haplotype analyses [Chen et al., 2011].

The role of the COMT Val/158/Met polymorphism in the modulation of cognitive performance and presumed prefrontal cortical function was first studied over 10 years ago [Egan et al., 2001]. Since that study, several lines of evidence point out dysfunction of COMT in the prefrontal cortex (PFC) as involved in psychotic symptoms and in the response to antipsychotic treatment [Molero et al., 2007; Wang et al., 2010]. Since clinical phenotypes rather than the whole spectrum of schizophrenia may be more closely related to certain susceptability genes, a quantitative trait test may lead to better understanding of the genotype–phenotype relationships in schizophrenic patients [Tao et al., 2006; Wang et al., 2010]. In the present study, therefore, we performed a case-control association study to assess whether a COMT haplotype and a specific genotype of the COMT gene influenced the clinical symptoms of schizophrenia as assessed using a quantitative trait test in Chinese patients with schizophrenia. The two SNPs selected for our investigation were rs 4818, which is located in exon 4 at 64 bp 3′ to Val158Met, and rs740603 within intron 1, which defines a synonymous A-G change that is about 6.1 kb 5′ to Val158Met. These two SNPs were chosen on the basis of the SZgene database (http://www.schizophreniaforum.org/res/sczgene/geneoverview.asp/geneid=420), the NCBI SNP database (www.ncbi.nlm.nih.gov/projects/SNP/), and a review of the literature, in order to have a minimum allele frequency (MAF) of 0.15. We also chose the synonymous COMT gene polymorphism rs4818 C/G, because recent evidence suggests that it accounts for greater variation in COMT activity than the functional Val158Met polymorphism [Nackley et al., 2006]. The COMT rs740603 was identified as another potentially functional variant, based on its positive selection in unrelated European-American and African-American populations [Ittiwut et al., 2011].

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Subjects

Two hundred and eight-four schizophrenia patients (male/female = 203/81) were recruited from Beijing Hui-Long-Guan hospital. Two independent experienced psychiatrists diagnosed each patient on the basis of the Structured Clinical Interview for DSM-IV (SCID). All schizophrenic patients were chronic, with at least 5 years of illness, were Han Chinese, and were between 25 and 75 years old (mean 48.3 ± 10.1 years). All patients had been receiving stable doses of oral antipsychotic drugs for at least 3 months before entry into the study. Antipsychotic drug treatment of the patients consisted mainly of monotherapy with clozapine (n = 119), risperidone (n = 83), perphenazine (n = 20), sulpiride (n = 19), chlorpromazine (n = 17), haloperidol (n = 12), with 14 patients on other agents. Each patient's mean daily dose of antipsychotics, including both the first- and the second-generation antipsychotics was converted to daily mean chlorpromazine milligram equivalents using standard guidelines [Woods, 2003; American Psychiatric Association, 2004]. The mean antipsychotic dose (in chlorpromazine equivalents) was 484 ± 506 mg/day. The patients had been on their respective medications for 44.2 ± 50.6 months at the time of the investigation.

Three hundred and twenty healthy Han Chinese controls (male/female = 140/180) without a current or past psychiatric history were selected from the local Beijing area. They were from 25 to 73 years old (mean 47.6 ± 12.4 years). A psychiatrist conducted psychiatric interviews to rule out psychiatric disorders among controls.

All subjects gave their written informed consent to participate in the study. The protocol was approved by the Institutional Review Board of the Beijing Hui-Long-Guan hospital.

Genotyping

We extracted genomic DNA for the polymerase chain reaction (PCR) from the whole blood sample using standard protocols.

According to the International SNP Consortium (http://www.ncbi.nlm.nih.gov=SNP) and Haploview software (http://www.hapmap.org), we selected 2 tag SNPs (rs740603 and rs4818) in the COMT gene. These two SNPs were determined using a restriction fragment length polymorphism (RFLP) assay after PCR amplification and digested with Mlu I or Bcl I, according to previously reported methods [Beuten et al., 2006; Roussos et al., 2008]. Genotyping was duplicated and carried out blindly to the clinical status.

Clinical Assessment

Four psychiatrists, who had previously completed a training session in rating the positive and negative syndrome scale (PANSS), assessed the patient's psychopathology using this scale. After training, they maintained an inter-rater correlation coefficient greater than 0.8 for the PANSS total score.

Statistical Analysis

Deviation from Hardy–Weinberg equilibrium was calculated by Chi-square tests. The differences of genotypic and allelic frequency between cases and controls were analyzed using SPSS 12.0. Bonferroni corrections were applied to each test to adjust for multiple testing. Other statistical analyses were done using UNPHASED 3.010, including linkage disequilibrium, haplotype analysis, and quantitative trait analysis. Quantitative trait analysis indicates the association of gene polymorphisms and severity of symptoms. The power (power defined as the chance that true differences will actually be detected) of the sample was calculated with Quanto Software [Gauderman, 2002], with known risk allele frequencies and a schizophrenia population prevalence of 0.01, and we examined log additive, recessive, and dominant models.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Table I shows that the patients and control subjects significantly differed in sex (P < 0.001) and smoking (P < 0.001). SNP rs740603 was genotyped in 284 patients and 320 controls, and SNP rs4818 in 277 patients and 290 controls. The χ2 goodness-of-fit test showed that the genotypic distributions of the two SNPs rs740603 and rs4818 in both patient and control groups were consistent with Hardy–Weinberg equilibrium (all P > 0.05). Analysis showed modest linkage disequilibrium between the two markers in both patients (D′ = 0.77, r2 = 0.47) and controls (D′ = 0.72, r2 = 0.39).

Table I. Demographics of Patients and Normal Control Subjects
 Schizophrenia (n = 284)Control subjects (n = 320)
  1. Note: Patients and control subjects significantly differed in sex (P < 0.001) and smoking (P < 0.001).

Sex, M/F203/81140/180
Age (years)48.3 ± 10.147.6 ± 12.4
Education (years)10.1 ± 8.110.4 ± 8.4
Body mass index (kg/m2)24.1 ± 4.524.6 ± 4.8
Smokers57.0%45.8%
Duration of illness (years)26.2 ± 9.7NA
Age of onset (years)23.9 ± 6.5NA
Hospitalization numbers3.6 ± 2.7NA
Duration of antipsychotic treatment (years)5.1 ± 4.6NA
PANSS NA
 Positive subscale10.7 ± 5.2 
 Negative subscale17.5 ± 7.2 
 General subscale21.9 ± 6.6 
 Total50.2 ± 15.7 

Table II shows no significant differences in the rs740603 and rs4818 genotype and allele distributions between the patient and control groups (both P > 0.05; Table II). In males we found a significant association between the rs4818 genotype and schizophrenia at the genotypic (χ2 = 8.035, df = 2, p = 0.018), but not at the allelic level (χ2 = 0.87, df = 1, P = 0.35). Furthermore, we found no significant overall difference in the estimated haplotype frequencies between cases and controls (χ2 = 1.891, df = 3, P = 0.59) or in any individual haplotype between cases and controls (all P > 0.05).

Table II. Comparison of Allele and Genotype Frequencies of Two COMT Polymorphisms Between Schizophrenic Cases and Controls
Group(n)Genotypic association(%)Allelic association(%)
  1. Bold indicates that there was a significant association between the rs4818 genotype and schizophrenia at the genotypic (χ2 = 8.035, df = 2, P = 0.018) in males.

rs740603 G/GA/GA/Aχ2PGAχ2P
AllCase(284)56(19.7)133(46.8)95(33.5)0.2360.888245(43.1)323(56.9)0.0110.915
Control(320)67(20.9)144(45.0)109(34.1)278(43.4)362(56.6)
MaleCase(203)35(17.2)101(49.8)67(33.0)2.5560.279171(42.1)235(57.9)0.0370.847
Control(140)31(22.1)58(41.4)51(36.4)120(42.9)160(57.1)
FemaleCase(81)21(25.9)32(39.5)28(34.6)1.8370.39974(45.7)88(54.3)0.1450.703
Control(180)36(20.0)86(47.8)58(32.2)158(43.9)202(56.1)
rs4818 G/GG/CC/Cχ2PGCχ2P
AllCase(277)37(13.4)132(47.7)108(39.0)3.6920.158206(37.2)348(62.8)0.5860.444
Control(290)44(15.2)115(39.7)131(45.2)203(35.0)377(65.0)
MaleCase(197)22(11.2)92(46.7)83(42.1)8.0350.018136(34.5)258(65.5)0.8670.352
Control(129)20(15.5)40(31.0)69(53.5)80(31.0)178(69.0)
FemaleCase(80)15(18.8)40(50.0)25(31.2)1.3990.49770(43.8)90(56.2)1.3720.241
Control(161)24(14.9)75(46.6)62(38.5)123(38.2)199(61.8)

Table III shows a significant association between negative symptoms and rs740603 (n = 284, P = 0.025, adjusted P = 0.032; effect size = 0.22), but not for rs4818 (n = 277, P = 0.054, adjusted P = 0.066; effect = 0.18). However, these results did not pass Bonferroni test. The rs740603 association with negative symptoms was stronger in females (χ2 = 8.782, P = 0.003, adjusted P = 0.007; Bonferroni correction P < 0.05; effect size = 0.41), but not significant in males (P > 0.05).

Table III. The Quantitative Trait Test for Association of two SNPs With Psychiatric Symptoms
 MeanVarianceχ2P
  1. Bold indicates a significant association between negative symptoms and rs740603 (χ2 = 5.037, df = 284, P = 0.025).

rs740603 (n = 284)
 Positive subscoreG = 10.48, A = 10.7347.980.1910.662
 Negative subscoreG = 16.29, A = 18.43125.95.0370.025
 General psychopathologyG = 21.28, A = 22.38141.21.1810.277
 Total scoreG = 47.69, A = 51.54762.92.6920.101
rs4818 (n = 277)
 Positive subscoreG = 10.78, C = 10.5047.500.2200.639
 Negative subscoreG = 16.32, C = 18.22125.73.6890.054
 General psychopathologyG = 21.70, C = 22.06142.90.1160.733
 Total scoreG = 48.37, C = 50.77766.30.9670.325

As shown in Table IV, further significant associations were identified between the rs740603-rs4818 haplotypes and negative symptoms (P = 0.045). This association remained statistically significant after 10,000 permutations (adjusted P = 0.039). Furthermore, negative symptoms were less severe in patients carrying the rs740603(G)-rs4818(G) haplotype than those patients with three other haplotypes (P = 0.01). We showed a significant association between the rs740603-rs4818 haplotypes and negative symptoms in females (P = 0.021; adjusted P = 0.037). Furthermore, negative symptoms were less severe in female patients carrying the rs740603(G)-rs4818(G) haplotype (P = 0.009). We showed no associations in male patients (data not shown). In addition, there were no significant differences in terms of dosage, type (typical vs. atypical antipsychotics), or duration of antipsychotic treatment in patients carrying the rs740603(G)-rs4818(G) haplotype than in those patients with three other haplotypes (all P > 0.05) in the combined patient groups or when the male and female patients were examined separately (all P > 0.05). Similarly, there were no significant differences in number of years of illness among the patients carrying the rs740603(G)-rs4818(G) haplotype than those patients with three other haplotypes (P > 0.05) in the combined patient groups or when the male and female patients were examined separately (both P > 0.05).

Table IV. The Quantitative Trait Test for Association of Haplotype With Negative Symptoms
HaplotypeMeanVarianceχ2P
rs740603-rs481817.41123.88.0390.045
GG15.80123.86.5940.010
GC17.85123.80.0000.987
AG20.95123.82.0250.152
AC18.41123.83.3400.068

This total sample had 0.77–0.84 power to detect dominant, recessive, and log additive polymorphic inheritance in schizophrenia with an odds ratio (OR) of 2 or greater (alpha = 0.05, two tailed test).

DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES

Two major findings evolved from the present study. (1) The COMT gene rs740603 and rs4818 polymorphisms did not seem to strongly contribute to the susceptibility to schizophrenia. (2) The COMT gene may be associated with negative symptoms in Han Chinese schizophrenic patients, especially females. Our finding of no association between the COMT rs740603 and rs4818 polymorphisms and schizophrenia is consistent with most previous studies. For example, recent meta-analyses found no evidence for a relationship between the COMT gene and schizophrenia [Fan et al., 2005; Munafo et al., 2005; Barnett et al., 2007]. Moreover, the COMT gene has generally not been associated with schizophrenia in several previous studies in the Han Chinese population including a recent study of 14 SNPs including two SNPs in our present study [Tsai et al., 2004; Yu et al., 2007; Chen et al., 2011].

A number of modifier genes may affect clinical features of schizophrenia without altering susceptibility to the illness [Fanous and Kendler, 2005], and our quantitative trait analysis showed that rs740603 was associated with negative symptoms, and the patients carrying allele A at rs740603 showed more negative symptoms. The rs4818 polymorphism alone showed only a trend (P = 0.054) association with negative symptoms, but the rs740603-rs4818 haplotypes were associated with negative symptoms, particularly in females. Patients carrying rs740603(G)-rs4818(G) scored lower than those with other haplotypes, which is consistent with the quantitative trait analysis for a single SNP. Our results suggest that the COMT gene may contribute to the severity of negative symptoms in Chinese Han schizophrenia.

Several authors have also found significant differences in negative symptoms in relation to the COMT genotype. For example, Pelayo-Teran et al. [2008] found that patients with a Val158 homozygote genotype had a higher severity of negative symptoms at the onset of the illness. Furthermore, they reported that the Val158 homozygote patients exhibited higher negative symptom severity scores after 6 weeks of treatment [Pelayo-Teran et al., 2011]. Also, Stefanis et al. [2004] found an association between the Val158 allele and negative schizotypy in a large non-psychotic sample. Another study also reported a higher severity of psychotic symptoms and a poorer improvement in negative symptoms to neuroleptic treatment in chronic schizophrenic patients with the Val/Val polymorphism [Molero et al., 2007]. Interestingly, a recent study showed an association of the rs4633-rs4680 haplotype of the COMT gene with negative symptoms in Han Chinese schizophrenics [Wang et al., 2010]. Taken together, COMT genetic variations seem to be involved in the negative symptoms of schizophrenia.

However, several authors have not found COMT genotypes related to any significant symptom differences [Inada et al., 2003; Koen et al., 2004; Tsai et al., 2004; Strous et al., 2006]. A recent study of 14 SNPs including the two SNPs in our present study found no association with the PANSS scores among schizophrenia patients in a Han population from Taiwan [Chen et al., 2011]. Such a discrepancy may be attributable to several reasons. First, population stratification could lead to a resetting of population gene frequencies. The sample from Taiwan may not be representative of the entire Han Chinese population, because of a possible population stratification bias [Yeh et al., 2010; Chen et al., 2011]. Second, the COMT genotypes can be regarded as trait-dependent features, while the assessment of illness intensity by PANSS is state-dependent. Therefore, a comparison of genotypes with the intensity of illness at any given time could be misleading. Our study's chronic schizophrenic inpatients had comparatively higher levels of negative symptoms compared to the outpatients, who had studied in Taiwan [Chen et al., 2011]. Hence, the differences in severity of clinical symptoms might be responsible for the discrepancy. Third, inconsistency can arise from differences in clinical subtypes of schizophrenia, in stages of disease progression (acute vs. chronic or active phase vs. remission), in illness courses, and in exposure to different types, dosages and durations of antipsychotic medications. The possible effects of antipsychotic treatment and illness duration on negative symptoms in our patients clearly distinguish the two studies. All patients had been receiving stable doses of oral antipsychotics for at least 3 months before entry into the study, and this medication could contribute to higher levels of negative symptoms [Kapur, 2004]. However, we found no association of the dose, type (atypical vs. typical antipsychotics), and duration of treatment with the haplotype rs740603(G)-rs4818(G) that was associated with negative symptoms. All our patients also were chronic, with at least 5 years of illness, but we found no significant difference in the number of years of illness among patients with the haplotype associated with negative symptoms.

This study has several limitations. First, we only genotyped two polymorphisms, while the total COMT gene variants in this 35 kb gene include at least 50 polymorphisms. Second, although we found the rs4818 genotype association with schizophrenia in males (P = 0.018), but not females, suggesting a sexual dimorphism between COMT variants and the genetic predisposition to schizophrenia [Shifman et al., 2002; Sazci et al., 2004; Pelayo-Teran et al., 2008; Hoenicka et al., 2010], the sample size is too weak to clarify this question. The positive result was based on 81 females with small numbers per genotype group. It is highly possible that we do see only false-positive results. Third, our sample size was comparatively small, and this could lead to false positive or negative results due to the lack of statistical power and selection of samples. It would be useful to extend the sample to about 800 subjects for a power of 0.80, with the relative risk of 2. This could help to clarify a possible association of the COMT rs740603/rs4818 polymorphisms and schizophrenia. Fourth, there were many samples that were not included in the genotype analysis of rs4818, and this might lead to bias in the statistical analysis due to the imbalance in the number of two SNPs in our current study. Fifth, population stratification or the unmatched sex of our samples could be confounders. However, the Chinese in Beijing are ethnically relatively homogenous, and our examination of ethnic markers showed no differences between the schizophrenics and controls. A replication study with genomic controls or a family-based population study would help to address this limitation. Sixth, a misclassification of genotypes is possible in spite of our quality controls, but such misclassification would typically bias the results toward no effect. Seventh, other polymorphisms could be functionally associated with schizophrenia or with the psychopathological symptoms of schizophrenia. Examining other functional variants of COMT is warranted.

In summary, our case-control association study did not provide support for COMT variants being associated with schizophrenia in a Chinese population. However, the COMT gene may contribute to the negative symptoms of schizophrenia in females. This finding remains preliminary due to limited sample size and our low statistical power and requires replication in larger samples in different ethnicities.

REFERENCES

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. REFERENCES
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