Multi-ancestry genome-wide association study of asthma exacerbations

Herrera-Luis, Esther, Ortega, Victor E, Ampleford, Elizabeth J, Sio, Yang Yie, Granell, Raquel, de Roos, Emmely, Terzikhan, Natalie, Vergara, Ernesto Elorduy, Hernandez-Pacheco, Natalia, Perez-Garcia, Javier
et al (show 53 more authors) (2022) Multi-ancestry genome-wide association study of asthma exacerbations. PEDIATRIC ALLERGY AND IMMUNOLOGY, 33 (6). e13802-.

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<h4>Background</h4>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.<h4>Methods</h4>A meta-GWAS of asthma exacerbations in 4989 Europeans, 2181 Hispanics/Latinos, 1250 Singaporean Chinese, and 972 African Americans analyzed 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10<sup>-5</sup> ) 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.<h4>Results</h4>One hundred and twenty-six independent variants were suggestively associated with asthma exacerbations in the discovery phase. Two variants independently replicated: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (OR<sub>T allele</sub> ) = 0.82, p = 9.05 × 10<sup>-6</sup> and replication: OR<sub>T allele</sub>  = 0.89, p = 5.35 × 10<sup>-3</sup> ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: OR<sub>C allele</sub>  = 0.85, p = 3.10 × 10<sup>-5</sup> and replication: OR<sub>C allele</sub>  = 0.89, p = 1.30 × 10<sup>-2</sup> ). Both variants regulate gene expression of genes where they locate and DNA methylation levels of nearby genes in whole blood.<h4>Conclusions</h4>This multi-ancestry study revealed novel suggestive regulatory loci for asthma exacerbations located in genomic regions participating in inflammation and host defense.

Item Type: Article
Uncontrolled Keywords: asthma exacerbations, EXTL2, GWAS, PANK1, single-nucleotide polymorphism
Divisions: Faculty of Health and Life Sciences
Faculty of Health and Life Sciences > Institute of Life Courses and Medical Sciences
Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology
Depositing User: Symplectic Admin
Date Deposited: 09 Jun 2022 13:42
Last Modified: 18 Jan 2023 21:00
DOI: 10.1111/pai.13802
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