Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations

Abstract

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.

Fig. 1

Summary of CAAPA ancestry and meta-analysis results. a CAAPA ADMIXTURE estimates: this panel summarizes the genome-wide proportions of ancestry for K = 3 populations, as estimated by the software program ADMIXTURE. A combined dataset of 20,482 overlapping and linkage disequilibrium pruned SNPs in 84 African (YRI, blue) and 84 European (CEU, red) 1000 Genomes Project phase 3 subjects, 43 Native American (green) subjects and 12,223 putatively unrelated CAAPA subjects were used to estimate these ancestry proportions. b QQ plot of the meta-analysis p-values: the plots in this panel are stratified by minor allele frequency (MAF) for low frequency and common SNPs. Inflation factors were calculated by transforming MR-MEGA association p-values to 1 degree of freedom (df) Chi-square statistics, and dividing the median of these statistics by the median of the theoretical Chi-square (1 df) distribution. The dashed black and red lines represent the upper and lower 95% confidence interval. c Manhattan plot of the meta-analysis p-values: the red, blue, and green horizontal lines in the Manhattan plot represent significant (MR-MEGA association p < 5 × 10⁻⁸), suggestive (MR-MEGA association p < 10⁻⁶), and candidate gene (MR-MEGA association p < 2.6 × 10⁻³) value thresholds, respectively. The candidate gene threshold is a Bonferroni-adjusted alpha level for 20 tests (1 locus from EVE, 1 locus from eMERGE, and 18 loci from TAGC). Windows of ±10 KB around the lead SNP at each selected locus are colored blue (EVE and eMERGE loci), red (TAGC loci), and purple (CAAPA loci with lead SNPs having p < 10⁻⁶). A larger window of ±200 KB is shown for the chromosome 17q12–21 locus

Fig. 2

Summary of the chromosome 17q12–21 region results. a This panel shows a locus zoom plot of the CAAPA meta-analysis results. Positions of 39 SNPs associated with asthma in TAGC Europeans that replicated in CAAPA (from Supplementary Table 13) are denoted by squares. The r² between the lead SNP rs907092 and the other SNPs with associations (represented by red, orange, green, light, and dark blue symbols) was calculated using African American subjects from the CAAPA WGS reference panel. The r² between the 39 SNPs in JAAS and GALA II are shown at the bottom of the plot, with darker shades of grey representing higher LD. JAAS and GALA II are the studies with the highest and lowest proportions of African ancestry, respectively. b A Forest plot of the effect size of rs907092 is shown in this panel. CAAPA datasets are ordered by decreasing percentage African ancestry. EAF effect allele frequency. %YRI, CEU, and NAT represent estimated mean percentage of African, European, and Native American ancestry, respectively. c This panel shows a box plot of the asthma risk allele odds ratio for 22 candidate SNPs in the chromosome 17q12–21 region. The 17 SNPs discussed by Stein et al. were selected, and an additional five SNPs from the CAAPA meta-analysis, with MR-MEGA association p < 10⁻⁶ and r² < 0.8 with all 17 selected SNPs in the 1000 Genomes Project European and African populations, were also included. These five additional SNPs are also expression quantitative trait loci for GSDMB/GSDMA/ORDLM3 in one or more GTEx tissues. The center line represents the median odds ratio, the box bounds represent the first and third quartile of the odds ratio distribution, and the whiskers are 1.5 times the first and third quartile odds ratio. Outliers are represented by circles