Mapping the 17q12–21.1 Locus for Variants Associated with Early-Onset Asthma in African Americans
Year: 2020
Type: article
Study design: Observational Study
Abstract: Rationale 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. Objectives To identify functional variants at 17q12–21.1 associated with early-onset asthma among African American individuals. Methods We evaluated African American participants from SAPPHIRE (Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race–Ethnicity) (n = 1,940), SAGE II (Study of African Americans, Asthma, Genes and Environment) (n = 885), and GCPD-A (Study of the Genetic Causes of Complex Pediatric Disorders–Asthma) (n = 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. Measurements and Main Results 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 GSDMB (gasdermin-B) transcripts. The phenome-wide association study 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.
Authors: Hongsheng Gui, Albert M. Levin, Donglei Hu, Patrick Sleiman, Shujie Xiao, Angel C. Y. Mak, Mao Yang, Andrea J. Barczak, Scott Huntsman, Celeste Eng, Samantha Hochstadt, Ellen Zhang, Kyle Whitehouse, Samantha Simons, Whitney Cabral, Sami Takriti, Gonçalo Abecasis, Thomas W. Blackwell, Hyun Min Kang, Deborah A. Nickerson, Soren Germer, David E. Lanfear, Frank Gilliland, W. James Gauderman, Rajesh Kumar, David J. Erle, Fernando D. Martinez, Hakon Hakonarson, Esteban G. Burchard, L. Keoki Williams
Institutions: Henry Ford Health, Children's Hospital of Philadelphia, University of Pennsylvania, University of Michigan, University of Washington, Brotman Baty Institute, New York Genome Center, University of Southern California, Northwestern University, University of Arizona, University of California, San Francisco
Language: English
Subfield: Physiology
Field: Medicine
Domain: Health Sciences
Open Access status: green
Funders: University of Washington, National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Environmental Health Sciences, National Institute on Minority Health and Health Disparities
Awards: G1052645489, G1268573537, G1278681517, G1648104072, G1678129981, G2096685756, Rare variants and NHLBI traits in deeply phenotyped cohorts, G2189466114, Addressing disparities in chronic disease with a teen and young adult focus, G2317004092, G232264632, G2816736420, G3194560040, G3256118428, Poly-omic Study of Asthma Exacerbations in Diverse Populations, G3858807296, G4432600228, G457392980, Mechanism of Endotoxin's Effect On Allergy Risk, G4831015605, Genetic Control of Airway Epithelium Gene Expression in Childhood Asthmatics, PHARMACOGENOMICS OF INHALED CORTICOSTEROID RESPONSIVENESS IN PATIENTS WITH ASTHMA, G6460128660, Combined Transcriptomics and Genomics to Find Asthma Genes in Admixed Populations, G6615318374, The Clinical Effectiveness of Pharmacy Adherence Information for Diabetes Control, Genes, air pollution, and asthma severity in minority children, G8008018803, Studies of Rare Genetic Variation in the Isolated Population of Sardinia, Southwest Environmental Health Sciences Center, Immune-driven Airway Epithelial Dysfunction in Muco-obstructive Asthma
OpenAlex ID: W3087792923