학술논문
African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans.
Document Type
Article
Author
Washington III, Charles; Dapas, Matthew; Biddanda, Arjun; Magnaye, Kevin M.; Aneas, Ivy; Helling, Britney A.; Szczesny, Brooke; Boorgula, Meher Preethi; Taub, Margaret A.; Kenny, Eimear; Mathias, Rasika A.; Barnes, Kathleen C.; CAAPA; Campbell, Monica; Figueiredo, Camila; Hansel, Nadia N.; Ober, Carole; Olopade, Christopher O.; Rotimi, Charles N.; Watson, Harold
Source
Subject
*AFRICAN American children
*AFRICAN Americans
*GENETIC variation
*EXOMES
*ASTHMA
*HAPLOTYPES
*ALLELES
*AFRICAN swine fever
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Language
ISSN
1756-994X
Abstract
Background: Asthma is the most common chronic disease in children, occurring at higher frequencies and with more severe disease in children with African ancestry. Methods: We tested for association with haplotypes at the most replicated and significant childhood-onset asthma locus at 17q12-q21 and asthma in European American and African American children. Following this, we used whole-genome sequencing data from 1060 African American and 100 European American individuals to identify novel variants on a high-risk African American–specific haplotype. We characterized these variants in silico using gene expression and ATAC-seq data from airway epithelial cells, functional annotations from ENCODE, and promoter capture (pc)Hi-C maps in airway epithelial cells. Candidate causal variants were then assessed for correlation with asthma-associated phenotypes in African American children and adults. Results: Our studies revealed nine novel African-specific common variants, enriched on a high-risk asthma haplotype, which regulated the expression of GSDMA in airway epithelial cells and were associated with features of severe asthma. Using ENCODE annotations, ATAC-seq, and pcHi-C, we narrowed the associations to two candidate causal variants that are associated with features of T2 low severe asthma. Conclusions: Previously unknown genetic variation at the 17q12-21 childhood-onset asthma locus contributes to asthma severity in individuals with African ancestries. We suggest that many other population-specific variants that have not been discovered in GWAS contribute to the genetic risk for asthma and other common diseases. [ABSTRACT FROM AUTHOR]