Mapping the 17q12-21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans.

Abstract

<b>Rationale:</b> The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower linkage disequilibrium in this region, which could facilitate identifying causal variants.<b>Objectives:</b> To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.<b>Methods:</b> We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-Ethnicity) (<i>n</i> = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (<i>n</i> = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders-Asthma) (<i>n</i> = 2,805). Associations with asthma onset at ages under 5 years were meta-analyzed across cohorts. The lead signal was reevaluated considering haplotypes informed by genetic ancestry (i.e., African vs. European). Both an expression-quantitative trait locus analysis and a phenome-wide association study were performed on the lead variant.<b>Measurements and Main Results:</b> The meta-analyzed results from SAPPHIRE, SAGE II, and the GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with the rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the expression-quantitative trait locus analysis, rs11078928 was related to alternative splicing of <i>GSDMB</i> (gasdermin-B) transcripts. The phenome-wide association study of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.<b>Conclusions:</b> A splice-acceptor polymorphism appears to be a causal variant for asthma at the 17q12-21.1 locus. This variant appears to have the same magnitude of effect in individuals of African and European descent.