Characterization of the Linkage Disequilibrium Structure and Identification of tagging-SNPs in Five DNA Repair Genes

BMC Cancer. 2005 Aug 9;5:99. doi: 10.1186/1471-2407-5-99.


Background: Characterization of the linkage disequilibrium (LD) structure of candidate genes is the basis for an effective association study of complex diseases such as cancer. In this study, we report the LD and haplotype architecture and tagging-single nucleotide polymorphisms (tSNPs) for five DNA repair genes: ATM, MRE11A, XRCC4, NBS1 and RAD50.

Methods: The genes ATM, MRE11A, and XRCC4 were characterized using a panel of 94 unrelated female subjects (47 breast cancer cases, 47 controls) obtained from high-risk breast cancer families. A similar LD structure and tSNP analysis was performed for NBS1 and RAD50, using publicly available genotyping data. We studied a total of 61 SNPs at an average marker density of 10 kb. Using a matrix decomposition algorithm, based on principal component analysis, we captured >90% of the intragenetic variation for each gene.

Results: Our results revealed that three of the five genes did not conform to a haplotype block structure (MRE11A, RAD50 and XRCC4). Instead, the data fit a more flexible LD group paradigm, where SNPs in high LD are not required to be contiguous. Traditional haplotype blocks assume recombination is the only dynamic at work. For ATM, MRE11A and XRCC4 we repeated the analysis in cases and controls separately to determine whether LD structure was consistent across breast cancer cases and controls. No substantial difference in LD structures was found.

Conclusion: This study suggests that appropriate SNP selection for an association study involving candidate genes should allow for both mutation and recombination, which shape the population-level genomic structure. Furthermore, LD structure characterization in either breast cancer cases or controls appears to be sufficient for future cancer studies utilizing these genes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Algorithms
  • Alleles
  • Ataxia Telangiectasia Mutated Proteins
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Cell Cycle Proteins / biosynthesis
  • Cell Cycle Proteins / genetics*
  • Computational Biology
  • DNA Repair Enzymes / biosynthesis
  • DNA Repair Enzymes / genetics*
  • DNA Repair*
  • DNA-Binding Proteins / biosynthesis
  • DNA-Binding Proteins / genetics*
  • Female
  • Gene Expression Regulation, Neoplastic*
  • Genes, BRCA1
  • Genes, BRCA2
  • Genetic Predisposition to Disease
  • Genotype
  • Haplotypes
  • Humans
  • Linkage Disequilibrium*
  • MRE11 Homologue Protein
  • Models, Genetic
  • Mutation
  • Nuclear Proteins / biosynthesis
  • Nuclear Proteins / genetics*
  • Polymorphism, Single Nucleotide*
  • Protein-Serine-Threonine Kinases / biosynthesis
  • Protein-Serine-Threonine Kinases / genetics*
  • Recombination, Genetic
  • Risk
  • Tumor Suppressor Proteins / biosynthesis
  • Tumor Suppressor Proteins / genetics*


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • MRE11 protein, human
  • NBN protein, human
  • Nuclear Proteins
  • Tumor Suppressor Proteins
  • XRCC4 protein, human
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • MRE11 Homologue Protein
  • Rad50 protein, human
  • DNA Repair Enzymes