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

Abstract

Bronchodilator (BD) drugs are commonly prescribed for treatment and management of obstructive lung function present with diseases such as asthma. Administration of BD medication can partially or fully restore lung function as measured by pulmonary function tests. The genetics of baseline lung function measures taken before BD medication have been extensively studied, and the genetics of the BD response itself have received some attention. However, few studies have focused on the genetics of post-BD lung function. To address this gap, we analyzed lung function phenotypes in 1103 subjects from the Study of African Americans, Asthma, Genes, and Environment, 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 (forced expiratory volume in 1 s [FEV₁ ], forced vital capacity [FVC], and FEV₁ /FVC) taken before and after albuterol BD administration on the same subjects, yielding six traits. We identified 18 GWAS loci, and five 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-BD lung function: ADAMTS1, RAD54B, and EGLN3.

Keywords: African American; GWAS; admixture; asthma; integrative genomic analysis; lung function.

FIGURE 1

Manhattan plots summarizing GWAS p values for all six lung function phenotypes. The solid red line denotes genome-wide significance (p < 9.95 × 10⁻⁸), while the dashed blue line marks the suggestive threshold (p < 1.99 × 10⁻⁶), per CODA calculations. Variants with a p value greater than 0.05 were deemed uninformative and therefore not plotted

FIGURE 2

A CANVIS plot of results from PAINTOR functional fine-mapping for locus 1, an association with pre-FEV₁ on chromosome 21. The SNP rs13615, which sits in the 3′-UTR of the gene ADAMTS1, attains a posterior probability of causality of 0.630. The panels show, from top to bottom, the posterior probability of causality; the five most informative functional annotations; GWAS p values; and local linkage disequilibrium expressed as a signed Pearson correlation. 3′-UTR, 3′-untranslated region; FEV₁, forced expiratory volume in 1 s; SNP, single nucleotide polymorphism

FIGURE 3

PAINTOR results for locus 2, an association on chromosome 4 with pre-FVC. The sentinel SNP, rs10857225, corresponds with a GWAS peak that does not pass Bonferroni correction for statistical significance. The highlighted peak tags the intron of the gene THAP6. FVC, forced vital capacity; SNP, single nucleotide polymorphism

FIGURE 4

PAINTOR fine-mapping results for locus 5, corresponding to a region on chromosome 14 associated with post-FVC. The most likely causal SNP, rs1351618, tags an intron of the gene EGLN3. FVC, forced vital capacity; SNP, single nucleotide polymorphism