Single nucleotide polymorphisms (SNPs) are usually the most frequent genomic variants. Directly pedigree-phased multi-SNP haplotypes provide a more accurate view of polymorphic population genomic structure than individual SNPs. The former are, therefore, more useful in genetic correlation with subject phenotype. We describe a new pedigree-based methodology for generating non-ambiguous SNP haplotypes for genetic study. SNP data for haplotype analysis were extracted from a larger Type 1 Diabetes Genetics Consortium SNP dataset based on minor allele frequency variation and redundancy, coverage rate (the frequency of phased haplotypes in which each SNP is defined) and genomic location. Redundant SNPs were eliminated, overall haplotype polymorphism was optimized and the number of undefined haplotypes was minimized. These edited SNP haplotypes from a region containing HLA-DRB1 (DR) and HLA-DQB1 (DQ) both correlated well with HLA-typed DR,DQ haplotypes and differentiated HLA-DR,DQ fragments shared by three pairs of previously identified megabase-length conserved extended haplotypes. In a pedigree-based genetic association assay for type 1 diabetes, edited SNP haplotypes and HLA-typed HLA-DR,DQ haplotypes from the same families generated essentially identical qualitative and quantitative results. Therefore, this edited SNP haplotype method is useful for both genomic polymorphic architecture and genetic association evaluation using SNP markers with diverse minor allele frequencies.
Keywords: HLA polymorphism; T1DGC; disease association; haplotype; major histocompatibility complex (MHC); pedigree; phase; protocol; single nucleotide polymorphism (SNP); type 1 diabetes (T1D).