Mapping the 17q12-21.1 Locus for Variants Associated with Early-onset Asthma in African Americans
Gui H, Levin AM, Hu D, Sleiman P, Xiao S, Mak AC, Yang M, Barczak AJ, Huntsman S, Eng C, Hochstadt S, Zhang E, Whitehouse K, Simons S, Cabral W, Takriti S, Abecasis G, Blackwell TW, Kang HM, Nickerson DA, Germer S, Lanfear DE, Gilliland F, Gauderman WJ, Kumar R, Erle DJ, Martinez FD, Hakonarson H, Burchard EG, and Williams LK. Mapping the 17q12-21.1 Locus for Variants Associated with Early-onset Asthma in African Americans. Am J Respir Crit Care Med 2020.
American journal of respiratory and critical care medicine
RATIONALE: The 17q12-21.1 locus is one of the most highly replicated genetic associations with asthma. Individuals of African descent have lower LD in this region, which could facilitate identifying causal variants.
OBJECTIVE: To identify functional variants at 17q12-21.1 associated with early-onset asthma among African American individuals.
METHODS AND MEASUREMENTS: We evaluated African American participants from the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE) (n=1,940), the Study of African Americans, Asthma, Genes & Environment (SAGE II) (n=885), and Study of the Genetic Causes of Complex Pediatric Disorders - Asthma (GCPD-A) (n=2,805). Associations with asthma onset at age(i.e., African vs. European). Both an expression quantitative trait locus (eQTL) analysis and phenome-wide association study (PheWAS) were performed on the lead variant.
MAIN RESULTS: The meta-analyzed results from SAPPHIRE, SAGE II, and GCPD-A identified rs11078928 as the top association for early-onset asthma. A haplotype analysis suggested that the asthma association partitioned most closely with rs11078928 genotype. Genetic ancestry did not appear to influence the effect of this variant. In the eQTL analysis, rs11078928 was related to alternative splicing of gasdermin-B (GSDMB) transcripts. The PheWAS of rs11078928 suggested that this variant was predominantly associated with asthma and asthma-associated symptoms.
CONCLUSIONS: 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.
ePub ahead of print