Hierarchical modeling of linkage disequilibrium: genetic structure and spatial relations

Am J Hum Genet. 2003 Feb;72(2):351-63. doi: 10.1086/346117. Epub 2003 Jan 13.

Abstract

Linkage disequilibrium (LD) mapping offers much promise for the positional cloning of disease-causing genes. However, conventional estimates of LD may fluctuate substantially across contiguous genomic regions, because of population-specific phenomena such as mutation, genetic drift, population structure, and variations in allele frequencies. This fluctuation makes it difficult to interpret patterns of LD and distinguish where a causal gene is located. To address this issue, we propose hierarchical modeling of LD (HLD) for fine-scale mapping. This approach incorporates information on haplotype block structure and chromosomal spatial relations to refine the pattern of LD, increasing the ability to localize disease genes. Here, we present a framework for HLD, a simulation study assessing the performance of HLD under various scenarios, and an application of HLD to existing data. This work demonstrates that hierarchical modeling of linkage disequilibrium is a valuable and flexible approach for fine-scale mapping.

Publication types

  • Comparative Study
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Chromosome Mapping
  • Chromosomes, Human, Pair 5
  • Computer Simulation
  • Crohn Disease / genetics
  • Gene Frequency
  • Genetic Drift
  • Genetic Markers
  • Genetic Structures
  • Genetics, Population
  • Haplotypes
  • Humans
  • Linkage Disequilibrium / genetics*
  • Models, Genetic*
  • Models, Theoretical*
  • Mutation
  • Polymorphism, Single Nucleotide

Substances

  • Genetic Markers