Admixture Mapping of Asthma in Southwestern Europeans with North African Ancestry Influences.

The prevalence of asthma symptoms in Canary Islanders, a southwestern European population from Spain, is almost three times higher than the country average. Because the genetic risks identified so far explain <5% of asthma heritability, here we aimed to discover new asthma loci by completing the first admixture mapping study in Canary Islanders leveraging their distinctive genetic makeup, where significant northwest African influences coexist in the European genetic diversity landscape. A 2-stage study was conducted in 1,491 unrelated individuals self-declaring having a Canary Islands origin for the 4 grandparents. Local ancestry estimates were obtained for the shared positions with reference data from putative ancestral populations from Europe, North Africa, and sub-Saharan Africa. Case-control deviations in local ancestry were tested for each ancestry separately using logistic regressions adjusted for principal components, followed by fine-mapping analyses based on imputed genotypes and analyses of the likely deleterious exonic variants. The admixture mapping analysis of asthma detected that local North African ancestry in a locus spanning 365 kb of chromosome 16q23.3 was associated with asthma risk at study-wide significance [lowest P = 1.12 × 10−4; odds ratio (OR) = 2.05; 95% confidence interval (CI) = 1.41–3.00]. Fine-mapping studies identified a variant associated with asthma, and results were replicated in independent samples (rs3852738, OR = 1.34; 95% CI = 1.13–1.59, P = 7.58 × 10−4). Whole exome sequencing data from a subset of individuals revealed an enrichment of likely deleterious variants among asthma cases in 16q23.3, particularly in the phospholipase Cγ2 ( PLCG2) gene ( P = 3.67 × 10−4). By completing the first mapping study of asthma in admixed populations from Europe, our results revealed a new plausible asthma locus.