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

Author:

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.,Barnes Kathleen C.,Campbell Monica,Figueiredo Camila,Hansel Nadia N.,Ober Carole,Olopade Christopher O.,Rotimi Charles N.,Watson Harold,Khurana Hershey Gurjit K.,Kercsmar Carolyn M.,Gereige Jessica D.,Makhija Melanie,Gruchalla Rebecca S.,Gill Michelle A.,Liu Andrew H.,Rastogi Deepa,Busse William,Gergen Peter J.,Visness Cynthia M.,Gold Diane R.,Hartert Tina,Johnson Christine C.,Lemanske Robert F.,Martinez Fernando D.,Miller Rachel L.,Ownby Dennis,Seroogy Christine M.,Wright Anne L.,Zoratti Edward M.,Bacharier Leonard B.,Kattan Meyer,O’Connor George T.,Wood Robert A.,Nobrega Marcelo A.,Altman Matthew C.,Jackson Daniel J.,Gern James E.,McKennan Christopher G.,Ober CaroleORCID,

Abstract

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.

Funder

HHMI Gilliam Fellowship

NIH

NIAID

Publisher

Springer Science and Business Media LLC

Subject

Genetics (clinical),Genetics,Molecular Biology,Molecular Medicine

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