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.

中文翻译：

---

非裔美国哮喘儿童的综合基因组分析发现了三个与肺功能相关的新位点


支气管扩张剂 (BD) 药物通常用于治疗和管理哮喘等疾病引起的阻塞性肺功能。根据肺功能测试的结果，服用 BD 药物可以部分或完全恢复肺功能。 BD 药物治疗之前采取的基线肺功能测量的遗传学已被广泛研究，并且 BD 反应本身的遗传学也受到了一些关注。然而，很少有研究关注 BD 后肺功能的遗传学。为了解决这一差距，我们使用综合基因组分析方法，结合了基因型、位点特异性遗传血统，分析了非裔美国人、哮喘、基因和环境研究（一个儿科哮喘病例对照队列）中 1103 名受试者的肺功能表型，以及功能注释信息。我们将全基因组关联研究 (GWAS) 结果与之前和之后进行的三项肺功能测试（1 秒用力呼气量 [FEV ₁ ]、用力肺活量 [FVC] 和 FEV ₁ /FVC）的混合映射扫描相结合沙丁胺醇 BD 对同一受试者施用，产生六种性状。我们从混合图谱中鉴定出 18 个 GWAS 基因座和另外 5 个基因座，涵盖了几个已知和新颖的肺功能候选基因。通过混合作图鉴定的大多数基因座在基因分型的全球人群中表现出次要等位基因频率的巨大差异。功能精细图谱揭示了外周血单核细胞、胎儿肺组织和肺成纤维细胞的表观遗传注释的丰富。我们的结果指出了BD前后肺功能的三个新的潜在遗传驱动因素： ADAMTS1 、 RAD54B和EGLN3 。