Genome-wide ancestry association testing identifies a common European variant on 6q14.1 as a risk factor for asthma in African American subjects

Abstract

Background: Genetic variants that contribute to asthma susceptibility might be present at varying frequencies in different populations, which is an important consideration and advantage for performing genetic association studies in admixed populations.

Objective: We sought to identify asthma-associated loci in African American subjects.

Methods: We compared local African and European ancestry estimated from dense single nucleotide polymorphism genotype data in African American adults with asthma and nonasthmatic control subjects. Allelic tests of association were performed within the candidate regions identified, correcting for local European admixture.

Results: We identified a significant ancestry association peak on chromosome 6q. Allelic tests for association within this region identified a single nucleotide polymorphism (rs1361549) on 6q14.1 that was associated with asthma exclusively in African American subjects with local European admixture (odds ratio, 2.2). The risk allele is common in Europe (42% in the HapMap population of Utah residents with Northern and Western European ancestry from the Centre d'Etude du Polymorphisme Humain collection) but absent in West Africa (0% in the HapMap population of Yorubans in Ibadan, Nigeria), suggesting the allele is present in African American subjects because of recent European admixture. We replicated our findings in Puerto Rican subjects and similarly found that the signal of association is largely specific to subjects who are heterozygous for African and non-African ancestry at 6q14.1. However, we found no evidence for association in European American or Puerto Rican subjects in the absence of local African ancestry, suggesting that the association with asthma at rs1361549 is due to an environmental or genetic interaction.

Conclusion: We identified a novel asthma-associated locus that is relevant to admixed populations with African ancestry and highlight the importance of considering local ancestry in genetic association studies of admixed populations.

Figure 1

Results of genome-wide ancestry and allelic association testing in African American adults with asthma and healthy controls using logistic regression. A. −log10 (p-values) across the genome showing the location of four ancestry association peaks with p-values < 0.01 (above the dashed line). B. Average local European ancestry in the cases (red) and controls (blue) on chromosome 6; vertical lines indicate the boundaries of the ancestry association peak with p<0.01, and the horizontal line indicates local European ancestry averaged across the genome. C. Tests of allelic association within the ancestry association peak on 6q in African Americans (using local ancestry as a covariate) and European Americans in CSGA/SARP.

Figure 2

QQplot comparing the observed distribution of p-values to a uniform distribution using the function qqplot in R for SNPs within the admixture mapping peak on chr6q. Local ancestry was included as a covariate in tests of association.

Figure 3

Tests of allelic association controlling for local ancestry within 500 Kb of rs1361549 in African Americans in CSGA/SARP at both genotyped and imputed SNPs from the 1000 Genomes Project.