title: Bayesian fine-scale mapping of disease loci, by hidden Markov models.
abstract: We present a new multilocus method for the fine-scale mapping of genes contributing to human diseases. The method is designed for use with multiple biallelic markers-in particular, single-nucleotide polymorphisms for which high-density genetic maps will soon be available. We model disease-marker association in a candidate region via a hidden Markov process and allow for correlation between linked marker loci. Using Markov-chain-Monte Carlo simulation methods, we obtain posterior distributions of model parameter estimates including disease-gene location and the age of the disease-predisposing mutation. In addition, we allow for heterogeneity in recombination rates, across the candidate region, to account for recombination hot and cold spots. We also obtain, for the ancestral marker haplotype, a posterior distribution that is unique to our method and that, unlike maximum-likelihood estimation, can properly account for uncertainty. We apply the method to data for cystic fibrosis and Huntington disease, for which mutations in disease genes have already been identified. The new method performs well compared with existing multi-locus mapping methods.
authors.affiliation: Department of Applied Statistics, University of Reading, United Kingdom. sns98am@reading.ac.uk
authors.forename: A P
authors.initials: AP
authors.lastname: Morris
authors.forename: J C
authors.initials: JC
authors.lastname: Whittaker
authors.forename: D J
authors.initials: DJ
authors.lastname: Balding
mesh_terms: D000483:Alleles; D001499:Bayes Theorem; D002874:Chromosome Mapping / Q000379:methods* / Q000706:statistics & numerical data*; D003550:Cystic Fibrosis / Q000235:genetics; D005787:Gene Frequency / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics*; D008040:Genetic Linkage / Q000235:genetics; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D006816:Huntington Disease / Q000235:genetics; D007700:Kinetics; D016013:Likelihood Functions; D008390:Markov Chains; D008957:Models, Genetic; D009154:Mutation / Q000235:genetics; D016017:Odds Ratio; D010641:Phenotype; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011995:Recombination, Genetic / Q000235:genetics; D016008:Statistical Distributions