Replication and fine mapping of asthma-associated loci in individuals of African ancestry

Abstract

Asthma originates from genetic and environmental factors with about half the risk of disease attributable to heritable causes. Genome-wide association studies, mostly in populations of European ancestry, have identified numerous asthma-associated single nucleotide polymorphisms (SNPs). Studies in populations with diverse ancestries allow both for identification of robust associations that replicate across ethnic groups and for improved resolution of associated loci due to different patterns of linkage disequilibrium between ethnic groups. Here we report on an analysis of 745 African-American subjects with asthma and 3,238 African-American control subjects from the Candidate Gene Association Resource (CARe) Consortium, including analysis of SNPs imputed using 1,000 Genomes reference panels and adjustment for local ancestry. We show strong evidence that variation near RAD50/IL13, implicated in studies of European ancestry individuals, replicates in individuals largely of African ancestry. Fine mapping in African ancestry populations also refined the variants of interest for this association. We also provide strong or nominal evidence of replication at loci near ORMDL3/GSDMB, IL1RL1/IL18R1, and 10p14, all previously associated with asthma in European or Japanese populations, but not at the PYHIN1 locus previously reported in studies of African-American samples. These results improve the understanding of asthma genetics and further demonstrate the utility of genetic studies in populations other than those of largely European ancestry.

Fig. 1

Manhattan plot of study results. Observed log-linear p values on the logarithmic scale are sorted by physical location on the 22 autosomes. Blue dots indicate loci with strong evidence of replication in African ancestry populations shown in Table 2 (color figure online)

Fig. 2

Fine mapping of association results at RAD50/IL13 locus. Association results in the CARe African-American samples with LD estimated either in African ancestry individuals (a) or European individuals (b) plotted using LocusZoom (Pruim et al. 2010) against the position on chromosome 5. The purple dot (also marked with a yellow arrowhead) represents the most significantly associated SNP after meta-analysis (rs17622991 for African-Americans and rs2244012 for Europeans). The SNPs surrounding the most significant SNP are color coded to reflect their LD with this SNP. Estimated recombination rates are plotted in cyan to reflect the local LD structure. Genes, the position of exons, and the direction of transcription from the UCSC genome browser are noted. Hashmarks represent SNP positions available in the meta-analysis (color figure online)

Fig. 3

Fine mapping of association results at ILlRLl/IL18R1 locus. Association results in the CARe African-American samples with LD estimated either in African ancestry individuals (a) or European individuals (b) plotted using LocusZoom (Pruim et al. 2010) against the position on chromosome 2. The purple dot (also marked with a yellow arrowhead) represents the most significantly associated SNP after meta-analysis (rs17027029 for African-Americans and rsl0173081 for Europeans). The SNPs surrounding the most significant SNP are color coded to reflect their LD with this SNP. Estimated recombination rates are plotted in cyan to reflect the local LD structure. Genes, the position of exons, and the direction of transcription from the UCSC genome browser are noted. Hashmarks represent SNP positions available in the meta-analysis (color figure online)