Hierarchical modeling of linkage disequilibrium: genetic structure and spatial relations.
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.
Conti
David V
DV
Department of Epidemiology and Biostatistics, Case Western Reserve University, Cleveland, OH, 44106, USA.
Witte
John S
JS
D002874:Chromosome Mapping; D002895:Chromosomes, Human, Pair 5; D003198:Computer Simulation; D003424:Crohn Disease / Q000235:genetics; D005787:Gene Frequency; D040961:Genetic Drift; D005819:Genetic Markers; D040342:Genetic Structures; D005828:Genetics, Population; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics*; D008957:Models, Genetic; D008962:Models, Theoretical; D009154:Mutation; D020641:Polymorphism, Single Nucleotide
D005819:Genetic Markers