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

Abstract

27Bronchodilator drugs are commonly prescribed for treatment and management of obstructive lung function 28 present with diseases such as asthma. Administration of bronchodilator medication can partially or fully restore 29 lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken 30 prior to bronchodilator medication has been extensively studied, and the genetics of the bronchodilator 31 response itself has received some attention. However, few studies have focused on the genetics of post-32 bronchodilator lung function. To address this gap, we analyzed lung function phenotypes in 1,103 subjects from 33 the Study of African Americans, Asthma, Genes, and Environment (SAGE), a pediatric asthma case-control 34 cohort, using an integrative genomic analysis approach that combined genotype, locus-specific genetic 35 ancestry, and functional annotation information. We integrated genome-wide association study (GWAS) results 36 with an admixture mapping scan of three pulmonary function tests (FEV1, FVC, and FEV1/FVC) taken before and 37 after albuterol bronchodilator administration on the same subjects, yielding six traits. We identified 18 GWAS 38 loci, and 5 additional loci from admixture mapping, spanning several known and novel lung function candidate 39 genes. Most loci identified via admixture mapping exhibited wide variation in minor allele frequency across 40 genotyped global populations. Functional fine-mapping revealed an enrichment of epigenetic annotations from 41 peripheral blood mononuclear cells, fetal lung tissue, and lung fibroblasts. Our results point to three novel 42 potential genetic drivers of pre-and post-bronchodilator lung function: ADAMTS1, RAD54B, and EGLN3. 43 Keywords 44 African-American, admixture, GWAS, lung function, asthma, integrative genomic analysis 45 130 total of six phenotypes were assessed for genotype association: pre-BD FEV1 (Pre-FEV1), pre-BD FVC (Pre-FVC), 131 pre-BD FEV1/FVC (Pre-FEV1/FVC), post-BD FEV1 (Post-FEV1), post-BD FVC (Post-FVC), and post-BD FEV1/FVC 132 (Post-FEV1/FVC). All phenotype values were normalized based on the expected lung function values calculated 133 from the Hankinson equations (Hankinson et al., 1999), which account for age, sex, height, and self-reported 134 ethnicity. Phenotype distributions were checked for normality and to detect outliers. Outliers were determined 135 using the method of Tukey fences (John Tukey, 1977). For each phenotype, we computed the first quartile value 136 (Q1), the third quartile value (Q3), and the interquartile range (IQR). We declared as outliers all values outside 137 of the range 138 ["1 − 3('"(), "3 + 3('"()].