Case-control admixture mapping in Latino populations enriches for known asthma-associated genes

Abstract

Background: Polymorphisms in more than 100 genes have been associated with asthma susceptibility, yet much of the heritability remains to be explained. Asthma disproportionately affects different racial and ethnic groups in the United States, suggesting that admixture mapping is a useful strategy to identify novel asthma-associated loci.

Objective: We sought to identify novel asthma-associated loci in Latino populations using case-control admixture mapping.

Methods: We performed genome-wide admixture mapping by comparing levels of local Native American, European, and African ancestry between children with asthma and nonasthmatic control subjects in Puerto Rican and Mexican populations. Within candidate peaks, we performed allelic tests of association, controlling for differences in local ancestry.

Results: Between the 2 populations, we identified a total of 62 admixture mapping peaks at a P value of less than 10(-3) that were significantly enriched for previously identified asthma-associated genes (P= .0051). One of the peaks was statistically significant based on 100 permutations in the Mexican sample (6q15); however, it was not significant in Puerto Rican subjects. Another peak was identified at nominal significance in both populations (8q12); however, the association was observed with different ancestries.

Conclusion: Case-control admixture mapping is a promising strategy for identifying novel asthma-associated loci in Latino populations and implicates genetic variation at 6q15 and 8q12 regions with asthma susceptibility. This approach might be useful for identifying regions that contribute to both shared and population-specific differences in asthma susceptibility.

FIG 1

Global ancestry proportions of Mexican (A) and Puerto Rican (B) subjects in the GALA study estimated by using ADMIXTURE (K = 3); included are the HapMap CEU, YRI, and 88 Native American subjects kindly provided by Mark Shriver (25 Aymaran, 24 Quechuan, 14 Nahuan, and 25 Mayan). Mexican subjects were, on average, 51% Native ancestry, 5% African ancestry, and 45% European ancestry, whereas Puerto Rican subjects were, on average, 13% Native ancestry, 20% African ancestry, and 67% European ancestry.

FIG 2

Admixture mapping in GALA Puerto Rican and Mexican subjects. The Manhattan plot for comparisons of local African ancestry in Mexican cases and control subjects shows a statistically significant peak on 6q15 based on 1000 permutations. Candidate admixture mapping peaks were defined as those with association P values of less than 10⁻³ (gray line). The complete set of Manhattan plots for all ancestries/populations is shown in Figs E1 and E2.

FIG 3

Admixture mapping quantile-quantile plot for genome-wide ancestry association testing of local African ancestry in Mexican cases and control subjects. Red points show the observed versus expected P values, and the gray shaded area represents the 95% quantile range of the permutations. Quantile-quantile plots for the other comparisons are shown in Fig E3.

FIG 4

Admixture mapping peak on 6q15 in Mexican subjects. African ancestry (left y-axis) is significantly lower in cases (red line) compared with control subjects (blue line, P = 1.3 × 10⁻⁶) at 6q15. The −log10 (P values) for genotyped (black circles) and imputed SNPs from the 1000 Genomes Project (gray circles) are indicated on the right y-axis. The location of genes within the peaks are indicated with green arrows indicating the direction of transcription.