A genome-wide association study on African-ancestry populations for asthma

Abstract

Background: Asthma is a complex disease characterized by striking ethnic disparities not explained entirely by environmental, social, cultural, or economic factors. Of the limited genetic studies performed on populations of African descent, notable differences in susceptibility allele frequencies have been observed.

Objectives: We sought to test the hypothesis that some genes might contribute to the profound disparities in asthma.

Methods: We performed a genome-wide association study in 2 independent populations of African ancestry (935 African American asthmatic cases and control subjects from the Baltimore-Washington, DC, area and 929 African Caribbean asthmatic subjects and their family members from Barbados) to identify single-nucleotide polymorphisms (SNPs) associated with asthma.

Results: A meta-analysis combining these 2 African-ancestry populations yielded 3 SNPs with a combined P value of less than 10(-5) in genes of potential biologic relevance to asthma and allergic disease: rs10515807, mapping to the alpha-1B-adrenergic receptor (ADRA1B) gene on chromosome 5q33 (3.57 x 10(-6)); rs6052761, mapping to the prion-related protein (PRNP) gene on chromosome 20pter-p12 (2.27 x 10(-6)); and rs1435879, mapping to the dipeptidyl peptidase 10 (DPP10) gene on chromosome 2q12.3-q14.2. The generalizability of these findings was tested in family and case-control panels of United Kingdom and German origin, respectively, but none of the associations observed in the African groups were replicated in these European studies. Evidence for association was also examined in 4 additional case-control studies of African Americans; however, none of the SNPs implicated in the discovery population were replicated.

Conclusions: This study illustrates the complexity of identifying true associations for a complex and heterogeneous disease, such as asthma, in admixed populations, especially populations of African descent.

Figure 1. Triangle plots showing estimated admixture in two populations of African descent

Estimates were performed using 416 ancestry informative markers (AIMs) and data from the International Hapmap Project on 60 YRI, 60 CEU, 90 CHB/JPT founders. The figure depicts ancestry in [A] 447 African American asthma cases and 459 non-asthmatic controls and [B] 298 African Caribbean founders.

Figure 2. Genome-wide associations for asthma in two populations of African descent

[A] African American asthmatic cases and controls; [B] African Caribbean families; [C] Meta-analysis of African American and African Caribbean GRAAD samples. (Note: For visual clarity, the Y-axis was truncated at −log₁₀(P-Value) = 9 resulting in the exclusion of a single data point; Panel A: rs13209883, P= 2.77 × 10^-11).

Figure 3. Evidence of association with asthma and linkage disequilibrium around ADRA1B, PRNP, and DPP10

Upper plots summarize association P-values for all genotyped and imputed SNPs in the African American case-control group for ADRA1B (Panel A), PRNP (Panel B), and DPP10 (Panel C). Lower plots illustrate patterns of linkage disequilibrium ( R²) in these samples; red squares for strong LD, blue squares for non-significant LD, and white squares for little or no LD.

Figure 4. Evidence of association with asthma and linkage disequilibrium around DPP10

Upper plot summarizes association P-values of genotyped and imputed SNPs for the African American cases and controls, African Caribbean families, and the European GABRIEL replicate population. Lower plots illustrate patterns of linkage disequilibrium (R²) in these samples; red squares for strong LD, blue squares for non-significant LD, and white squares for little or no LD.