Significant evidence for linkage to chromosome 5q13 in a genome-wide scan for asthma in an extended pedigree resource

Abstract

Asthma is a multifactorial disease with undetermined genetic factors. We performed a genome-wide scan to identify predisposition loci for asthma. The asthma phenotype consisted of physician-confirmed presence or absence of asthma symptoms. We analyzed 81 extended Utah pedigrees ranging from three to six generations, including 742 affected individuals, ranging from 2 to 40 per pedigree. We performed parametric multipoint linkage analyses with dominant and recessive models. Our analysis revealed genome-wide significant evidence of linkage to region 5q13 (log of the odds ratio (LOD)=3.8, recessive model), and suggestive evidence for linkage to region 6p21 (LOD=2.1, dominant model). Both the 5q13 and 6p21 regions indicated in these analyses have been previously identified as regions of interest in other genome-wide scans for asthma-related phenotypes. The evidence of linkage at the 5q13 region represents the first significant evidence for linkage on a genome-wide basis for this locus. Linked pedigrees localize the region to approximately between 92.3-105.5 Mb.

Figure 1

Results of genome-wide scan for asthma, het-TLOD plotted, x axis represents the chromosome. The solid line depicts results from the dominant model and the dashed line depicts the recessive model.

Figure 2

Shared linked-haplotype segments as delimited by estimated recombination events plotted against bp position for each of the 16 pedigrees linked to chromosome 5q13 region, ordered by maximum by-pedigree LOD score in this region. The three-recombinant boundaries are depicted by the horizontal dashed lines. The locations of the maximum by-pedigree LOD scores are shown as horizontal ticks along the plotted vertical line for each pedigree. The value of the maximum LOD score for each pedigree is given below the plot. The numbers in parentheses indicate the number of affected individuals in each pedigree who could clearly be determined to share two of the hypothesized segregating predisposition haplotypes, and the total number of affected individuals.

Figure 3

Shared linked-haplotype segments as delimited by estimated recombination events plotted against bp position for each of the seven pedigrees linked to chromosome 6p21 region, ordered by maximum by-pedigree LOD score in this region. The three-recombinant boundaries are depicted by the dashed lines. The locations of the maximum by-pedigree LOD scores are shown as horizontal ticks along the plotted regions for each pedigree. The value of the maximum LOD score for each pedigree is given below the plot. The numbers in parentheses indicate the number of affected individuals in each pedigree who share the hypothesized segregating predisposition haplotype, and the total number of affected individuals.