Haplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.

TitleHaplotypes at ATM identify coding-sequence variation and indicate a region of extensive linkage disequilibrium.
Publication TypeJournal Article
Year of Publication2000
AuthorsBonnen, PE, Story, MD, Ashorn, CL, Buchholz, TA, Weil, MM, Nelson, DL
JournalAm J Hum Genet
Date Published2000 Dec
KeywordsAlgorithms, Alleles, Animals, Ataxia Telangiectasia, Ataxia Telangiectasia Mutated Proteins, Case-Control Studies, Cell Cycle Proteins, Codon, DNA-Binding Proteins, Ethnicity, Europe, Gene Frequency, Genetic Variation, Haplotypes, Hominidae, Humans, Linkage Disequilibrium, Molecular Sequence Data, Polymorphism, Single Nucleotide, Protein Serine-Threonine Kinases, Racial Groups, Recombination, Genetic, Tumor Suppressor Proteins

Genetic variation in the human population may lead to functional variants of 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 studies. We developed haplotypes consisting of 14 biallelic neutral-sequence variants that span 142 kb of the ATM locus. ATM is the gene responsible for the autosomal recessive disease ataxia-telangiectasia (AT). These ATM noncoding single-nucleotide polymorphisms (SNPs) were genotyped in nine CEPH families (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 frequencies > or = .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 found in the study population of European ancestry, in which no evidence for recombination could be discerned. The potential of ATM haplotypes for detection of genetic variants through association studies was tested by analysis of 84 individuals carrying one of three ATM coding SNPs. Each coding SNP was detected by association with an ATM haplotype. We demonstrate that association studies with haplotypes for candidate genes have significant potential for the detection of genetic backgrounds that contribute to disease.

Alternate JournalAm J Hum Genet
PubMed ID11078475
PubMed Central IDPMC1287921
Grant ListR01 CA075432 / CA / NCI NIH HHS / United States
T15 LM007093 / LM / NLM NIH HHS / United States
1T15LM07093 / LM / NLM NIH HHS / United States
CA75432 / CA / NCI NIH HHS / United States

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