Haplotypes at ATM identify coding-sequence variation and indicate a regionof extensive linkage disequilibrium

Genetic variation in the human population may lead to functional variants o f genes that contribute to risk for common chronic diseases such as cancer. In an effort to detect such possible predisposing variants, we constructed haplotypes for a candidate gene and tested their efficacy in association s tudies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible fo r the autosomal recessive disease ataxia-telangiectasia (AT). These ATM non coding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH f amilies (89 individuals) and in 260 DNA samples from four different ethnic origins. Analysis of these data with an expectation-maximization algorithm revealed 22 haplotypes at this locus, with three major haplotypes having fr equencies greater than or equal to .10. Tests for recombination and linkage disequilibrium (LD) show reduced recombination and extensive LD at the ATM locus, in all four ethnic groups studied. The most striking example was fo und in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detec tion of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP w as detected by association with an ATM haplotype. We demonstrate that assoc iation studies with haplotypes for candidate genes have significant potenti al for the detection of genetic backgrounds that contribute to disease.