The trimmed-haplotype test for linkage disequilibrium

Citation
Cj. Maclean et al., The trimmed-haplotype test for linkage disequilibrium, AM J HU GEN, 66(3), 2000, pp. 1062-1075
Citations number
29
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Molecular Biology & Genetics
Journal title
AMERICAN JOURNAL OF HUMAN GENETICS
ISSN journal
00029297 → ACNP
Volume
66
Issue
3
Year of publication
2000
Pages
1062 - 1075
Database
ISI
SICI code
0002-9297(200003)66:3<1062:TTTFLD>2.0.ZU;2-Y
Abstract
Single-marker linkage-disequilibrium (LD) methods cannot fully describe dis equilibrium in an entire chromosomal region surrounding a disease allele. W ith the advent of myriad tightly linked microsatellite markers, we have an opportunity to extend LD analysis from single markers to multiple-marker ha plotypes. Haplotype analysis has increased statistical power to disclose th e presence of a disease locus in situations where it correctly reflects the historical process involved. For maximum efficiency evidence of LD ought t o come not just from a single haplotype, which may well be rare, but in add ition from many similar haplotypes that could have descended from the same ancestral founder but have been trimmed in succeeding generations. We prese nt such an analysis, called the "trimmed-haplotype method." We focus on chr omosomal regions that are small enough that disequilibrium in significant p ortions of them may have been preserved in some pedigrees and yet that cont ain enough markers to minimize coincidental occurrence of the haplotype in the absence of a disease allele: perhaps regions 1-2 cM in length. In gener al, we could have no idea that haplotype an ancestral founder carried gener ations ago, nor do we usually have a precise chromosomal location for the d isease-susceptibility locus. Therefore, we must search through all possible haplotypes surrounding multiple locations. Since such repeated testing obl iterates the sampling distribution of the test, me employ bootstrap methods to calculate significance levels. Trimmed-haplotype analysis is performed on family data in which genotypes have been assembled into haplotypes. It c an be applied either to conventional parent-affected-offspring triads or to multiplex pedigrees. We present a method for summarizing the LD evidence, in any pedigree, that can be employed in trimmed-haplotype analysis as well as in other methods.