We report here on the detection of nine single nucleotide polymorphisms (SNPs) near to the NOTCH4 locus in the search for schizophrenia susceptibility genes in the class III region of the human major histocompatibility complex (MHC). We totally analyzed 122 family trios recruited in the UK. The TDT analysis demonstrated that of the nine SNPs, three were associated with schizophrenia, including rs1009382 (P = 0.00047), rs204887 (P = 0.007), and rs8283 (P = 0.015). Both rs1009382 and rs204887 are present in the TNXB locus. The rs1009382 is a non-synonymous SNP located in exon 23 of the gene and its A to G base change causes a Glu2578Gly substitution. The goodness-of-fit test showed that genotypic distribution of rs1009382 was deviated from Hardy-Weinberg equilibrium due to homozygote excess in the patient group (P = 0.01), suggesting that a double dose of a genetic risk may be involved. Possibly, rs1009382 is a candidate SNP predisposing to a schizophrenic illness. Moreover, the test for linkage disequilibrium (LD) between paired SNPs showed that the nine SNPs studied may be in the same LD block with an unexpected pattern as the strength of LD was not correlated with the distance between paired SNPs. The haplotype analysis suggested that there might be more than one disease-related allele located in the class III region of the MHC, and that these alleles possibly confer either susceptibility or resistance to schizophrenia.
Copyright 2003 Wiley-Liss, Inc.