Targeted analysis of genomic regions enriched in African ancestry reveals novel classical HLA alleles associated with asthma in Southwestern Europeans

Abstract

Despite asthma has a considerable genetic component, an important proportion of genetic risks remain unknown, especially for non-European populations. Canary Islanders have the largest African genetic ancestry observed among Southwestern Europeans and the highest asthma prevalence in Spain. Here we examined broad chromosomal regions previously associated with an excess of African genetic ancestry in Canary Islanders, with the aim of identifying novel risk variants associated with asthma susceptibility. In a two-stage cases-control study, we revealed a variant within HLA-DQB1 significantly associated with asthma risk (rs1049213, meta-analysis p = 1.30 × 10^-7, OR [95% CI] = 1.74 [1.41-2.13]) previously associated with asthma and broad allergic phenotype. Subsequent fine-mapping analyses of classical HLA alleles revealed a novel allele significantly associated with asthma protection (HLA-DQA1*01:02, meta-analysis p = 3.98 × 10^-4, OR [95% CI] = 0.64 [0.50-0.82]) that had been linked to infectious and autoimmune diseases, and peanut allergy. HLA haplotype analyses revealed a novel haplotype DQA1*01:02-DQB1*06:04 conferring asthma protection (meta-analysis p = 4.71 × 10^-4, OR [95% CI] = 0.47 [0.29- 0.73]).

Figure 1

Manhattan plot of meta-analysis results for the association study of chromosome 6 region (grey) and the classical HLA alleles (blue). The y-axis displays transformed p-values (–log10) while the x-axis represents chromosome positions (GRCh37/hg19). The horizontal lines correspond to the significance thresholds of each study after Bonferroni correction: the upper for the targeted association (p = 1.20 × 10^–6) and the lower for the classical HLA alleles mapping (p = 4.50 × 10^–4). The significant variants are highlighted in orange (targeted association testing of SNPs) and red (fine mapping of classical HLA alleles). The code used to plot the data was obtained from HATK.

Figure 2

Plot of the first two principal components (explaining 78.95% of variability) of the individuals analysed in stage 1 and 2, projected on data of African (AFR), East Asian (EAS), European (EUR), and South Asian (SAS) populations from The 1000 Genomes Project.