Haplotype tagging for the identification of common disease genes

Genome-wide linkage disequilibrium (LD) mapping of common disease genes cou ld be more powerful than linkage analysis if the appropriate density of pol ymorphic markers were known and if the genotyping effort and cost of produc ing such an LD map could be reduced. Although different metrics that measur e the extent of LD have been evaluated(1-3), even the most recent studies(2 ,4) have not placed significant emphasis on the most informative and cost-e ffective method of LD mapping-that based on haplotypes. We have scanned 135 kb of DNA from nine genes, genotyped 122 single-nucleotide polymorphisms ( SNPs; approximately 184,000 genotypes) and determined the common haplotypes in a minimum of 384 European individuals for each gene. Here we show how k nowledge of the common haplotypes and the SNPs that tag them can be used to (i) explain the often complex patterns of LD between adjacent markers, (ii ) reduce genotyping significantly (in this case from 122 to 34 SNPs), (iii) scan the common variation of a gene sensitively and comprehensively and (i v) provide key fine-mapping data within regions of strong LD. Our results a lso indicate that, at least for the genes studied here, the current version of dbSNP would have been of limited utility for LD mapping because many co mmon haplotypes could not be defined. A directed re-sequencing effort of th e approximately 10% of the genome in or near genes in the major ethnic grou ps would aid the systematic evaluation of the common variant model of commo n disease.