Retrospective Ancestral Recombination Graphs with Applications to Gene Mapping

Linda Hartman and Ola Hössjer

Abstract:: Rare diseases are often investigated in case-control studies. For the purpose of gene mapping, sampled case and control genotypes are compared at a set of marker locations. Closely linked marker loci can be handled by modeling the genealogy of the sample. We present such a model, which splits the chromosomes into subpopulations. In this way the model accounts for the ascertainment process, where cases are typically over sampled. The model is used for multipoint gene mapping by means of a LOD score. The LOD score copes with arbitrary phenotypes and genetic models, allows for neutral mutations, and adapts to marker allele frequencies. Under certain model approximations we develop a permutation based test that is computationally feasible, even when haplotype phase is unknown.

Key words:: Association analysis; multipoint; unknown haplotype phase; ascertainment; case-control study; coalescent; identical by descent (IBD); sampling; SNP; LOD score;