African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans

Authors

Charles Washington, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Matthew Dapas, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Arjun Biddanda, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Kevin M. Magnaye, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Ivy Aneas, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Britney A. Helling, Department of Human Genetics, The University of Chicago, 928 E. 58th St. CLSC 507C, Chicago, IL, 60637, USA.
Brooke Szczesny, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Meher Preethi Boorgula, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.
Margaret A. Taub, Department of Biostatistics, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, USA.
Eimear Kenny, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
Rasika A. Mathias, Department of Medicine, Johns Hopkins University, Baltimore, MD, USA.
Kathleen C. Barnes, Department of Medicine, University of Colorado Denver, Aurora, CO, USA.

Document Type

Journal Article

Publication Date

9-29-2022

Journal

Genome medicine

Volume

14

Issue

1

DOI

10.1186/s13073-022-01114-x

Keywords

Asthma; Fine mapping; Health disparities; Integrated omics; Whole-genome sequencing

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.

APA Citation

Washington, 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.; and Barnes, Kathleen C., "African-specific alleles modify risk for asthma at the 17q12-q21 locus in African Americans" (2022). GW Authored Works. Paper 1583.
https://hsrc.himmelfarb.gwu.edu/gwhpubs/1583

Department

Pediatrics