Susceptibility to spina bifida; an association study of five candidate genes

Authors

  • K. MORRISON,

    1. MRC Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK
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  • C. PAPAPETROU,

    1. MRC Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK
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  • F. A. HOL,

    1. University Hospital Nijmegen, 417 Department of Human Genetics, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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  • E. C. M. MARIMAN,

    1. University Hospital Nijmegen, 417 Department of Human Genetics, Geert Grooteplein 10, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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  • S. A. LYNCH,

    1. Department of Human Genetics, University of Newcastle upon Tyne, 19/20 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK
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  • J. BURN,

    1. Department of Human Genetics, University of Newcastle upon Tyne, 19/20 Claremont Place, Newcastle upon Tyne, NE2 4AA, UK
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  • Y. H. EDWARDS

    Corresponding author
    1. MRC Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK
      Prof. Yvonne H. Edwards, MRC Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK. Tel. 0171 380 7777 x5042; Fax 0171 387 3496. E-mail: yedwards@hgmp.mrc.ac.uk
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Prof. Yvonne H. Edwards, MRC Human Biochemical Genetics Unit, University College London, Wolfson House, 4 Stephenson Way, London NW1 2HE, UK. Tel. 0171 380 7777 x5042; Fax 0171 387 3496. E-mail: yedwards@hgmp.mrc.ac.uk

Abstract

Clues regarding candidate genes which influence susceptibility to spina bifida and anencephaly come from the identification of folate-associated risk factors and from studies of mouse mutants showing neural tube anomalies. On this basis we selected five candidate genes; CBS, MS, MTHFR, T (Brachyury) and BRCA1 for genetic analysis in 31 Dutch and 48 British NTD families. Ten polymorphisms, two for each gene, were used in transmission tests for disequilibrium (TDT). In six instances more than 50 transmissions from heterozygous parents could be examined. Using TDT we find evidence for an association between an allele at the T gene and liability to NTD in the embryo. Data from British and Dutch populations showed the same trend and in combination gave a χ2TDT=4.89, P=0.03 (OR 2.39, CI 95% 1.02–5.61). No association, in either population group, was found for CBS, MS and MTHFR, the enzymes most directly associated with the known risk factors in folate metabolism. The possibility of complex genetic interactions was explored; the data show that a Gly919 MS variant occurs more frequently in combination with the MTHFR thermolabile variant in mothers of NTD offspring (OR 3.94, CI 95% 1.0–16.3).

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