Integrative genomic analysis in African American children with asthma finds 3 novel loci associated with lung function

Abstract: Bronchodilator drugs are commonly prescribed for treatment and management of obstructive lung function present with diseases such as asthma. Administration of bronchodilator medication can partially or fully restore lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken prior to bronchodilator medication has been extensively studied, and the genetics of the bronchodilator response itself has received some attention. However, few studies have focused on the genetics of post-bronchodilator lung function. To address this gap, we analyzed lung function phenotypes in 1,103 subjects from the Study of African Americans, Asthma, Genes, and Environment (SAGE), a pediatric asthma case-control cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results with an admixture mapping scan of three pulmonary function tests (FEV1, FVC, and FEV1/FVC) taken before and after albuterol bronchodilator administration on the same subjects, yielding six traits. We identified 18 GWAS loci, and 5 additional loci from admixture mapping, spanning several known and novel lung function candidate genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel potential genetic drivers of pre- and post-bronchodilator lung function: ADAMTS1, RAD54B, and EGLN3.