A spatial probit model for fine-scale mapping of disease genes.
We present a novel statistical method for linkage disequilibrium (LD) mapping of disease susceptibility loci in case-control studies. Such studies exploit the statistical correlation or LD that exist between variants physically close along the genome to identify those that correlate with disease status and might thus be close to a causative mutation, generally assumed unobserved. LD structure, however, varies markedly over short distances because of variation in local recombination rates, mutation and genetic drift among other factors. We propose a Bayesian multivariate probit model that flexibly accounts for the local spatial correlation between markers. In a case-control setting, we use a retrospective model that properly reflects the sampling scheme and identify regions where single- or multi-locus marker frequencies differ across cases and controls. We formally quantify these differences using information-theoretic distance measures while the fully Bayesian approach naturally accommodates unphased or missing genotype data. We demonstrate our approach on simulated data and on real data from the CYP2D6 region that has a confirmed role in drug metabolism.
De Iorio
Maria
M
Department of Epidemiology and Public Health, Imperial College London, London, UK. m.deiorio@imperial.ac.uk
Verzilli
Claudio J
CJ
D001499:Bayes Theorem; D016022:Case-Control Studies; D002874:Chromosome Mapping / Q000379:methods*; D002892:Chromosomes, Human, Pair 22; D019389:Cytochrome P-450 CYP2D6 / Q000235:genetics*; D005787:Gene Frequency; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics*; D015810:Linkage Disequilibrium / Q000235:genetics*; D008957:Models, Genetic
D019389:Cytochrome P-450 CYP2D6