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Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population

Molecular Psychiatry volume 7, pages 446–447 (2002)Cite this article

SIR – Catechol-O-methyltransferase (COMT) is a major component of the metabolic pathways of neurotransmitters such as dopamine, adrenaline, and noradrenaline. It has long been considered as a candidate for vulnerability to schizophrenia in view of both its function and location in the genome. Direct evidence implicating the COMT locus has come from association studies among Caucasian, Japanese and Chinese cohorts, although the results are conflicting. Recently, Li and colleagues1 reported a significant association between COMT and schizophrenia. Applying a family-based study design, they analysed two dinucleotide repeats and six SNPs at the COMT locus for transmission distortion in 198 Chinese schizophrenic family trios and found marker and haplotype transmission distortion. Their results support the hypotheses that either COMT is itself a susceptibility gene, or that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles. It is worthwhile noting that exon 4 of COMT contains a G to A missense mutation that results in a substitution of Met for Val at codon 108 (Val108Met), that decreases the activity level of the COMT enzyme 3- to 4-fold. The alleles are codominant, as heterozygous individuals have enzyme activity that is midway between homozygote individuals. It has been suggested that the COMT Val108 allele increases prefrontal dopamine catabolism, impairs prefrontal cognition and physiology and by this mechanism slightly increases risk for schizophrenia. Egan et al also found a significant increase in transmission of the Val allele to the schizophrenic offspring in their 104 trios.2 To further investigate the role of COMT in schizophrenia susceptibility, we tested the transmission of five SNP markers in the COMT gene region from parents to schizophrenic offspring in 166 Chinese family trios. The extent of linkage disequilibrium between the polymorphisms was investigated, and individual markers and haplotypes were analysed for transmission distortion in the family trios using the transmission disequilibrium test (TDT).3 No preferential transmission of any allele or haplotype was detected for any of the polymorphisms. These data suggested that the COMT gene is unlikely to play a major role in the aetiology of schizophrenia in the Chinese population.

Parent-offspring trios consisting of schizophrenic probands and their biological parents were selected. The probands included 64 females and 102 males (mean age 22, SD ± 6.2) from Shanghai, East China.4 Subjects with schizophrenia were strictly diagnosed according to the criteria of DSM-III-R. All the probands were inpatient schizophrenics interviewed by psychiatrists, diagnosis was independently verified and checked by two independent senior psychiatrists who reviewed the patients’ medical casenotes before they were included in the study. Written informed consent was obtained from the patient and their relatives after the procedure had been fully explained. All subjects were Han Chinese in origin. Five SNP polymorphisms were genotyped in 166 family trios by PCR using standard PCR-RFLP analysis. For the Pml I, Bcl I, Nla III and Bgl I RFLPs, genotypes were determined similarly to previously described methods described by Karayiorgou and colleagues.5 For the Hind III RFLP, genotypes were determined as the methods described by Li Tao and colleagues.1 Mendelian inheritance was also carried out. The transmission disequilibrium test (TDT) was applied to test if the marker locus and the hypothetical disease locus were linked or in linkage disequilibrium.3 The TDT for individual markers was performed using the ETDT program.6

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References

  1. Li T et al. Mol Psychiatry 2000 5: 77–84

  2. Egan MF et al. Proc Natl Acad Sci U S A 2001 98: 6917–6922

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Authors and Affiliations

  1. Shanghai Research Center of Life Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai, 200031, China

    J B Fan, W Y Chen, J X Tang, S Li & L He

  2. Mental Health Research Institute, University of Michigan, Ann Arbor, 48109, MI, USA

    S Li

  3. Shanghai Institute of Mental Health, 600 South Wan Ping Road, Shanghai, China

    N F Gu & G Y Feng

  4. Dept of Mental Health, University of Aberdeen, Medical School, Foresterhill, Aberdeen, AB25 2ZD, UK

    G Breen & D St Clair

  5. Bio-X Life Science Research Center, Shanghai Jiao Tong University, Shanghai, China

    J B Fan, W Y Chen, J X Tang & L He

Authors
  1. J B Fan
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  2. W Y Chen
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  3. J X Tang
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  4. S Li
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  6. G Y Feng
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  8. D St Clair
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  9. L He
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Correspondence to L He.

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Fan, J., Chen, W., Tang, J. et al. Family-based association studies of COMT gene polymorphisms and schizophrenia in the Chinese population. Mol Psychiatry 7, 446–447 (2002). https://doi.org/10.1038/sj.mp.4001001

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