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

Abstract

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.

Figure 1

Schematic representation of the standard Lander-Green algorithm.

Figure 2

Schematic representation of the Lander-Green algorithm, with clustering of neighboring markers.

Figure 3

Founder allele graphs used to identify possible haplotype states for a pedigree. A, Summary of the observed genotype data for two markers. B, Possible inheritance vector or genetic descent graph. Genotyped alleles are shown in gray, and the connections they induce between founder alleles are denoted with dashed lines. C, Representation of the founder allele graph corresponding to panels A and B. D, Possible haplotype states, calculated as the Cartesian product of possible states for each founder allele graph component.

Figure 4

Analysis of affected sibship data with one parent genotyped, with and without the modeling of LD. This simulated data set included 500 sibships, each with three affected siblings and one genotyped parent.

Figure 5

Analysis of exemplary psoriasis data set