Identification of novel single nucleotide polymorphisms within the NOTCH4 gene and determination of association with MHC alleles.

Mapping of disease susceptibility loci within the MHC has been partly hampered by the high degree of polymorphism of the HLA genes and the high level of linkage disequilibrium (LD) between markers within the MHC region. It is therefore important to identify new markers and determine the level of LD between HLA alleles and non-HLA genes. The NOTCH4 gene lies at the centromeric end of the MHC class III region, approximately 335 kb telomeric of the DRB1 locus. The encoded protein is an oncogene that is important in regulating vascular development and remodelling. A recent report has linked polymorphisms within NOTCH4 with risk of developing schizophrenia. We have investigated if coding polymorphisms exist within this gene and have identified three single nucleotide polymorphisms; a synonomous T to C transition at +1297 (HGBASE accession number SNP000064386), a synonomous A to G transition at +3061 (SNP000064387) and an A to G transition at +3063 which results in a replacement of glycine with aspartic acid at amino acid 279 (SNP000064388). The allele frequencies of +1297T, +3061A and +3063G were 0.65, 0.66 and 0.66, respectively. Linkage disequilibrium was detected both between these markers and with MHC alleles. These findings can be used in the fine mapping of disease susceptibility alleles within the MHC.