Genomewide screen and identification of gene-gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma

Abstract

The genomewide screen to search for asthma-susceptibility loci, in the Collaborative Study on the Genetics of Asthma (CSGA), has been conducted in two stages and includes 266 families (199 nuclear and 67 extended pedigrees) from three U.S. populations: African American, European American, and Hispanic. Evidence for linkage with the asthma phenotype was observed for multiple chromosomal regions, through use of several analytical approaches that facilitated the identification of multiple disease loci. Ethnicity-specific analyses, which allowed for different frequencies of asthma-susceptibility genes in each ethnic population, provided the strongest evidence for linkage at 6p21 in the European American population, at 11q21 in the African American population, and at 1p32 in the Hispanic population. Both the conditional analysis and the affected-sib-pair two-locus analysis provided further evidence for linkage, at 5q31, 8p23, 12q22, and 15q13. Several of these regions have been observed in other genomewide screens and linkage or association studies, for asthma and related phenotypes. These results were used to develop a conceptual model to delineate asthma-susceptibility loci and their genetic interactions, which provides a promising basis for initiation of fine-mapping studies and, ultimately, for gene identification.

Figure 1

Results of genomewide screen for asthma-susceptibility loci. Allele-sharing multipoint LOD scores are shown, and the marker identification is given for LOD scores >1. Results for the total CSGA data set are shown in the top graph, followed by the results for each ethnic group.

Figure 2

Results of conditional analyses for asthma-susceptibility loci, for the total CSGA data set. The genomewide conditional analysis was performed four times, conditional on the evidence for linkage to each of the chromosomes 1, 6, 11, and 14. Allele-sharing multipoint LOD scores are shown, and marker identification is given at the peak LOD-score values.

Figure 3

Summary of conditional analysis of 266 CSGA families: conditional on chromosome 11q21, a positive relationship was observed with loci on 12q22 and 8p23; conditional on 14q32, a positive relationship was observed for 12q22 and 15q13; and, conditional on 1p32, a positive relationship was observed for 8p23, 15q13, and 5q31.