SIR—Catechol-O-methyltransferase (COMT) gene has been considered to be one of the candidate genes for schizophrenia because it encodes one of the major enzymes for dopamine metabolism and also lies on chromosome band 22q11.2, which has long been associated with schizophrenia susceptibility.1 COMT has a common functional polymorphism, a single-nucleotide polymorphism at position 108/158 that results in a change from valine (Val) to methionine (Met); the Val variant has a higher enzymatic activity, leading to increased degradation of dopamine.2 The association of this COMT Val108/158Met polymorphism with schizophrenia has long been a focus of genetic studies into schizophrenia. However, the results of studies of this genetic variant in schizophrenic subjects are inconsistent. Recently, Munafo et al3 demonstrated that there was evidence of a significant association between the COMT Val allele and schizophrenia risk, when all case–control studies were included in a meta-regression. However, when only studies that reported allele frequencies in the controls that did not deviate significantly from Hardy–Weinberg equilibrium were included, these results were no longer significant. As case–control studies carry an increased risk of confounding by population stratification, the family-based designs could be a more reliable method to test the possible implication of the COMT Val108/158Met polymorphism in schizophrenia susceptibility. In a meta-analysis of family-based association studies, Glatt et al4 reported that the Val allele may be a small but reliable risk factor for schizophrenia in the Caucasian population, but the influence of this polymorphism on risk in Asian populations (from three studies; two with Chinese subjects and one with Japanese participants) remains unclear. In the study of a Chinese population, Li et al5 first reported an excess transmission of the Val allele among 178 family trios with schizophrenia. However, this finding was not reproduced in a subsequent study of 166 Chinese schizophrenia trios.6
To further clarify the role of COMT in schizophrenia in the Chinese population, we tested the transmission of the COMT Val108/158Met polymorphism in 220 trios consisting of Han Chinese schizophrenic subjects and their biological parents. All patients (91 female subjects and 129 male subjects; mean age 30.3 (SD±8.2) years) were psychiatric in-patients diagnosed from relevant criteria identified at interview and in medical records according to the Diagnostic and Statistical Manual of the American Psychiatric Association (DSM-IV). The diagnoses were re-evaluated by a senior psychiatrist. The method for genotyping the COMT Val108/158Met polymorphism is detailed in our previous report.7 The study was approved by the Institution Review Board of the Taipei Veterans General Hospital and informed consent was obtained from each participant in advance.
In this family-based study of COMT Val158Met polymorphism in schizophrenia, Val/Val is the most common genotype, followed by Val/Met (Val/Val, 103 (46.8%); Val/Met, 97 (44.1%); Met/Met, 20 (9.1%)). The distribution of these genotypes within both the probands and parents were in Hardy–Weinberg equilibrium. Transmission disequilibrium test analysis in 220 trios (196 heterozygous parents) demonstrated no significant difference between transmitted (Met, 103; Val, 93) and nontransmitted (Met, 93; Val, 103) allele frequency for this COMT Val108/158Met polymorphism (χ=0.510; P=0.457). Combining our data with the two previous studies of Chinese family trios with schizophrenia still showed no preferential transmission of any allele (χ=0.367, P=0.545; Table 1).
Our family-based study, similar to the study of Chinese participants by Fan et al,6 showed no association between the COMT Val108/158Met polymorphism and schizophrenia, and therefore does not support the earlier Chinese family-based study that does describe a significant correlation.5 Combining the three studies (564 schizophrenia trios; 461 heterozygous parents) also failed to reveal an association, suggesting that the COMT Val108/158Met polymorphism is not implicated in schizophrenia susceptibility in the Chinese population. A previous report suggested that the Val allele might be a small but reliable risk factor for schizophrenia in the Caucasian population;4 however, this analysis was based on two small-scale family-based studies (total 267 trios). The negative findings in the Chinese population call for more family-based studies in the Caucasian population to confirm the association of COMT Val108/158Met polymorphism with schizophrenia. Although our results do not provide evidence supporting the proposed relationship between schizophrenia and the COMT Val108/158Met polymorphism, given the assumption that schizophrenia is probably multiply determined, the sample size of the present study may not have been large enough to exclude involvement of a polymorphism with weak effect. Furthermore, in our study sample, to detect the difference between 93/196 and 103/196 with power 0.5, the minimum sample size should be 778. Similarly, to detect the difference between 237/461 and 224/461 in the sample from three Chinese studies with power 0.5, the minimum sample size should be 2487. If a higher power is desired, say, 0.8, then the required minimum sample size would be much greater than those two figures above.
In this study, we only tested COMT Val108/158Met polymorphism in a family-based association study. There is some evidence that the COMT haplotype has additional predictive power for COMT expression.8, 9 In support of this suggestion, Shifman et al10 found schizophrenia linkage only to a Val158-containing haplotype. Thus, further research into genotyping more markers and using a haplotype-based approach is needed to definitively characterise the role of COMT gene in the pathogenesis of schizophrenia.
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Lotta T et al. Kinetics of human soluble and membrane-bound catechol O-methyltransferase: a revised mechanism and description of the thermolabile variant of the enzyme. Biochemistry 1995; 34: 4202–4210.
Munafo MR et al. Lack of association of the COMT (Val(158/108) Met) gene and schizophrenia: a meta-analysis of case–control studies. Mol Psychiatry 2005; 10: 765–770.
Glatt SJ et al. Association between a functional catechol O-methyltransferase gene polymorphism and schizophrenia: meta-analysis of case-control and family-based studies. Am J Psychiatry 2003; 160: 469–476.
Li T et al. Preferential transmission of the high activity allele of COMT in schizophrenia. Psychiatr Genet 1996; 6: 131–133.
Fan JB et al. Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population. Mol Psychiatry 2002; 7: 446–447.
Tsai SJ et al. Association study of a functional catechol-O-methyltransferase genetic polymorphism with age of onset, cognitive function, symptomatology and prognosis in chronic schizophrenia. Neuropsychobiology 2004; 49: 196–200.
Bray NJ et al. A haplotype implicated in schizophrenia susceptibility is associated with reduced COMT expression in human brain. Am J Hum Genet 2003; 73: 152–161.
Zhu G et al. Differential expression of human COMT alleles in brain and lymphoblasts detected by RT-coupled 5′ nuclease assay. Psychopharmacology 2004; 177: 178–184.
Shifman S et al. A highly significant association between a COMT haplotype and schizophrenia. Am J Hum Genet 2002; 71: 1296–1302.
This work was supported by Grant CH-91-16 from the Cheng-Hsin Rehabilitation and Medical Center, and Grant VGH-90-238 from the Taipei Veterans General Hospital.
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Tsai, SJ., Hong, CJ., Hou, SJ. et al. Lack of association of catechol-O-methyltransferase gene Val108/158Met polymorphism with schizophrenia: a family-based association study in a Chinese population. Mol Psychiatry 11, 2–3 (2006). https://doi.org/10.1038/sj.mp.4001736
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