Multi-ancestry genome-wide association study of asthma exacerbations.

Abstract

Asthma exacerbations are a serious public health concern due to high healthcare resource utilization, work/school productivity loss, impact on quality of life, and risk of mortality. The genetic basis of asthma exacerbations has been studied in several populations, but no prior study has performed a multi-ancestry meta-analysis of genome-wide association studies (meta-GWAS) for this trait. We aimed to identify common genetic loci associated with asthma exacerbations across diverse populations and to assess their functional role in regulating DNA methylation and gene expression. A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6million genetic variants. Suggestively associated variants (p≤5×10-5 ) were assessed for replication in 36,477 European and 1078 non-European asthma patients. Functional effects on DNA methylation were assessed in 595 Hispanic/Latino and African American asthma patients and in publicly available databases. The effect on gene expression was evaluated in silico. One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010located atvascular cell adhesion molecule-1/exostosin likeglycosyltransferase-2 (VCAM1/EXTL2)(discovery: odds ratio (ORT allele )=0.82, p=9.05×10-6 and replication: ORT allele =0.89, p=5.35×10-3 ) and rs943126 frompantothenate kinase1 (PANK1) (discovery: ORC allele =0.85, p=3.10×10-5 and replication: ORC allele =0.89, p=1.30×10-2 ). Both variants regulate gene expressionof genes where they locate and DNA methylation levels of nearby genes in whole blood. This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.