An urgent call to collect data related to COVID-19 and Indigenous populations globally

Abstract

<h3>Introduction</h3> Bronchodilator response (BDR) is a measurement of acute bronchodilation in response to short-acting β2-agonists (SABA), with a heritability between 10–40%. Identifying genetic variants associated with BDR may lead to a better understanding of its complex pathophysiology. <h3>Methods</h3> We performed a genome-wide association study (GWAS) of BDR in six adult cohorts with participants of European ancestry (EA) and African ancestry (AA) including community cohorts and cohorts ascertained on the basis of obstructive pulmonary disease. Validation analysis was carried out in two pediatric asthma cohorts. <h3>Results</h3> A total of 10,623 EA and 3,597 AA participants were included in the analyses. No single nucleotide polymorphism (SNP) was associated with BDR at the conventional genome-wide significance threshold (p&lt;5×10⁻⁸). Performing fine-mapping and using a threshold of p&lt;5×10⁻⁶ to identify suggestive variants of interest, we identified three SNPs with possible biological relevance: rs35870000 (within <i>FREM1</i>)<i>,</i> which may be involved in IgE- and IL5-induced changes in airway smooth muscle cell responsiveness; rs10426116 (within <i>ZNF284</i>)<i>,</i> a zinc finger protein, which have been implicated in asthma and BDR previously; rs4782614 (near <i>ATP2C2)</i>, involved in calcium transmembrane transport. Validation in pediatric cohorts yielded no significant SNPs, possibly due to age-genotype interaction effects. <h3>Conclusion</h3> Ancestry-stratified and ancestry-combined GWAS meta-analyses of over 14,000 participants did not identify genetic variants associated with BDR at the genome-wide significance threshold, although a less stringent threshold identified three variants showing suggestive evidence of association. A common definition and protocol for measuring BDR in research may improve future efforts to identify variants associated with BDR.