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Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11

Molecular Psychiatry volume 5, pages 77–84 (2000)Cite this article

A Corrigendum to this article was published on 30 June 2000

Abstract

Family-based linkage disequilibrium mapping using SNP markers is expected to be a major route to the identification of susceptibility alleles for complex diseases. However there are a number of methodological issues yet to be resolved, including the handling of extended haplotype data and analysis of haplotype transmission in sib-pair or family trio samples. In the present study, we have analysed two dinucleotide repeat and six SNP markers at the COMT locus at chromosome 22q11, a region implicated in psychosis, for transmission distortion in 198 Chinese schizophrenic family trios. When individual markers were analysed using the TDT, two showed modest evidence of transmission distortion (186C/T, P = 0.04; Val158Met, P = 0.01). Using haplotypes of paired markers analysed by the program TRANSMIT, the most significant P value was 0.001, for the Met158Val and 900ins/delC polymorphisms in the COMT gene. The global P value for the haplotypes of all six SNP markers tested was 0.004, largely a result of the excess transmission of two extended haplotypes which differed at the marker 408C/G. The exclusion of this marker from the analysis gave a global P value of 0.002 and produced a five marker haplotype system which was significant at P = 0.0006. This haplotype consisted of the alleles −287G:186C:Val158:900insC:ARVCF930C, which may represent a background haplotype for the transmission of a schizophrenia susceptibility allele at chromosome 22q11. Our results support the hypotheses that either COMT is itself a susceptibility gene, or more likely that this region of chromosome 22 contains a susceptibility gene that is in linkage disequilibrium with COMT alleles.

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Acknowledgements

We are grateful for a NARSAD independent investigator Award to DAC, which principally funded this work, and for a Wellcome Trust Biomedical Research Collaboration grant to DAC and XL. We are also grateful for the support of the Wellcome Trust to PCS and JZ, and the China National Natural Sciences Foundation, The Doctoral Fund of the Chinese National Committee of Education and the New York China Medical Board (TL).

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  1. Department of Psychological Medicine, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    T Li, D Ball, J Zhao, R M Murray, P C Sham & D A Collier

  2. Department of Psychiatry, West China University of Medical Sciences, Sichuan, 610041, PR China

    T Li & X Liu

  3. Centre for Social, Genetic and Developmental Psychiatry, The Institute of Psychiatry, De Crespigny Park, Denmark Hill, London, SE5 8AF, UK

    D Ball & P C Sham

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Correspondence to D A Collier.

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Li, T., Ball, D., Zhao, J. et al. Family-based linkage disequilibrium mapping using SNP marker haplotypes: application to a potential locus for schizophrenia at chromosome 22q11. Mol Psychiatry 5, 77–84 (2000). https://doi.org/10.1038/sj.mp.4000638

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