Genome-wide association study in minority children with asthma implicates DNAH5 in bronchodilator responsiveness

Abstract

Variability in response to short-acting β₂-agonists (e.g., albuterol) among patients with asthma from diverse racial/ethnic groups may contribute to asthma disparities. We sought to identify genetic variants associated with bronchodilator response (BDR) to identify potential mechanisms of drug response and risk factors for worse asthma outcomes. Genome-wide association studies of bronchodilator response (BDR) were performed using TOPMed Whole Genome Sequencing data of the Asthma Translational Genomic Collaboration (ATGC), which corresponded to 1136 Puerto Rican, 656 Mexican and 4337 African American patients with asthma. With the population-specific GWAS results, a trans-ethnic meta-analysis was performed to identify BDR-associated variants shared across the three populations. Replication analysis was carried out in three pediatric asthma cohorts, including CAMP (Childhood Asthma Management Program; n = 560), GACRS (Genetics of Asthma in Costa Rica Study; n = 967) and HPR (Hartford-Puerto Rico; n = 417). A genome-wide significant locus (rs35661809; P = 3.61 × 10^-8) in LINC02220, a non-coding RNA gene, was identified in Puerto Ricans. While this region was devoid of protein-coding genes, capture Hi-C data showed a distal interaction with the promoter of the DNAH5 gene in lung tissue. In replication analysis, the GACRS cohort yielded a nominal association (1-tailed P < 0.05). No genetic variant was associated with BDR at the genome-wide significant threshold in Mexicans and African Americans. Our findings help inform genetic underpinnings of BDR for understudied minority patients with asthma, but the limited availability of genetic data for racial/ethnic minority children with asthma remains a paramount challenge.

Figure 1

Manhattan plots of BDR GWAS results for (a) Puerto Ricans, (b) Mexicans, (c) African Americans, and (d) trans-ethnic meta-analysis. Top 5 loci of each result were annotated with the nearest protein-coding genes. The green horizontal dashed line indicates a genome-wide significance threshold of 5 × 10^–8.

Figure 2

Evidence supporting DNAH5 as a BDR-associated gene in Puerto Ricans. (a) eQTL (top) from the GTEx v8 release, regional associations in the GWAS (middle), and a chromatin interaction in lung tissue (bottom) from the Capture Hi-C data. (b) differential expression results for DNAH5 using the GEO data.