Handling marker-marker linkage disequilibrium: Pedigree analysis with clustered markers

Single-nucleotide polymorphisms (SNPs) are rapidly replacing microsatellites as the markers of choice for genetic linkage studies and many other studies of human pedigrees. Here, we describe an efficient approach for modeling linkage disequilibrium (LD) between markers during multipoint analysis of human pedigrees. Using a gene-counting algorithm suitable for pedigree data, our approach enables rapid estimation of allele and haplotype frequencies within clusters of tightly linked markers. In addition, with the use of a hidden Markov model, our approach allows for multipoint pedigree analysis with large numbers of SNP markers organized into clusters of markers in LD. Simulation results show that our approach resolves previously described biases in multipoint linkage analysis with SNPs that are in LD. An updated version of the freely available Merlin software package uses the approach described here to perform many common pedigree analyses, including haplotyping and haplotype frequency estimation, parametric and nonparametric multipoint linkage analysis of discrete traits, variance-components and regression-based analysis of quantitative traits, calculation of identity-by-descent or kinship coefficients, and case selection for follow-up association studies. To illustrate the possibilities, we examine a data set that provides evidence of linkage of psoriasis to chromosome 17.