Identity-by-descent estimation and mapping of qualitative traits in large, complex pedigrees

Abstract

Computing identity-by-descent sharing between individuals connected through a large, complex pedigree is a computationally demanding task that often cannot be done using exact methods. What I present here is a rapid computational method for estimating, in large complex pedigrees, the probability that pairs of alleles are IBD given the single-point genotype data at that marker for all individuals. The method can be used on pedigrees of essentially arbitrary size and complexity without the need to divide the individuals into separate subpedigrees. I apply the method to do qualitative trait linkage mapping using the nonparametric sharing statistic S(pairs). The validity of the method is demonstrated via simulation studies on a 13-generation 3028-person pedigree with 700 genotyped individuals. An analysis of an asthma data set of individuals in this pedigree finds four loci with P-values <10(-3) that were not detected in prior analyses. The mapping method is fast and can complete analyses of approximately 150 affected individuals within this pedigree for thousands of markers in a matter of hours.

Figure 1.—

Pedigree used to compute the accuracy of the IBD estimation method. The number of alleles shared IBD was estimated for the pair of individuals (solid symbols).

Figure 2.—

Approximate vs. exact estimates of the number of alleles shared IBD for the pair of individuals in Figure 1 (solid symbols) for a (A) the SNP marker, (B) the microsatellite marker, and (C) the haplotype marker.

Figure 3.—

Histogram of the true S_pairs statistic (top) and of the statistic as computed from simulated data (bottom).

Figure 4.—

Histogram of the true S_pairs statistic (top) and of the bias-corrected statistic as computed from simulated data (bottom). Both distributions have been scaled to have equal variance.

Figure 5.—

QQ plot of 10,000 values of for the SNP marker (vertical axis) and the microsatellite marker (horizontal axis).

Figure 6.—

QQ plot of 10,000 values of for the haplotype marker vs. (A) the microsatellite marker and (B) the SNP marker.