Multilocus linkage disequilibrium mapping by the decay of haplotype sharing with samples of related individuals.
We consider the problem of multilocus linkage disequilibrium (LD) mapping of a trait-associated variant from case-control samples in which some individuals may be related. Our method, which we call DHS-R, is an extension of the decay of haplotype sharing (DHS) method of McPeek and Strahs and Strahs and McPeek. The DHS-R method shares the main features of the DHS method: (1) it allows construction of a confidence interval for the location of a trait-associated variant; (2) it allows for missing observations and unphased genotype data, with the uncertainty in the haplotypes taken into account in the analysis; and (3) it allows for heterogeneity, mutation, recombination, and background LD. The main advances of the DHS-R are (1) the ability to include individuals of arbitrary known relationship (including inbreeding) in the case and control samples; (2) an extension to allow partially-phased haplotypes derived from case-parent trio genotype data; and (3) an extension to allow for genotyping error in the model. Our method, which uses a hidden Markov model for likelihood calculation and maximization, has the advantage of being computationally feasible even in a large, complex pedigree. Simulations based on a 13-generation, 1,623-member Hutterite pedigree demonstrate accurate coverage of the confidence intervals for location of the variant. We apply the method to fine-mapping of a susceptibility locus for bronchial hyperresponsiveness (BHR) in the Hutterites. The results confirm the importance of taking into account the relatedness of individuals in LD mapping.
Zhang
Jian
J
Department of Statistics, University of Chicago, Chicago, Illinois 60637, USA.
Schneider
Daniel
D
Ober
Carole
C
McPeek
Mary Sara
MS
D000465:Algorithms; D000483:Alleles; D016535:Bronchial Hyperreactivity / Q000235:genetics; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods*; D003198:Computer Simulation; D016001:Confidence Intervals; D005787:Gene Frequency; D014644:Genetic Variation / Q000235:genetics; D005838:Genotype; D006239:Haplotypes / Q000235:genetics*; D006801:Humans; D016013:Likelihood Functions; D015810:Linkage Disequilibrium / Q000235:genetics*; D008390:Markov Chains; D008957:Models, Genetic; D009154:Mutation; D010375:Pedigree; D011995:Recombination, Genetic