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

01 Jun 2022
Herrera-Luis E, Ortega VE, Ampleford EJ, Sio YY, Granell R, de Roos E, Terzikhan N, Vergara EE, Hernandez-Pacheco N, Perez-Garcia J, Martin-Gonzalez E, Lorenzo-Diaz F, Hashimoto S, Brinkman P, U-BIOPRED Study Group, Jorgensen AL, Yan Q, Forno E, Vijverberg SJ, Lethem R, Espuela-Ortiz A, Gorenjak M, Eng C, González-Pérez R, Hernández-Pérez JM, Poza-Guedes P, Sardón O, Corcuera P, Hawkins GA, Marsico A, Bahmer T, Rabe KF, Hansen G, Kopp MV, Rios R, Cruz MJ, González-Barcala FJ, Olaguibel JM, Plaza V, Quirce S, Canino G, Cloutier M, Del Pozo V, Rodriguez-Santana JR, Korta-Murua J, Villar J, Potočnik U, Figueiredo C, Kabesch M, Mukhopadhyay S, Pirmohamed M, Hawcutt DB, Melén E, Palmer CN, Turner S, Maitland-van der Zee AH, von Mutius E, Celedón JC, Brusselle G, Chew FT, Bleecker E, Meyers D, Burchard EG, Pino-Yanes M


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 9.6 million genetic variants. Suggestively associated variants (p ≤ 5 × 10 ) 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: rs12091010 located at vascular cell adhesion molecule-1/exostosin like glycosyltransferase-2 (VCAM1/EXTL2) (discovery: odds ratio (OR ) = 0.82, p = 9.05 × 10 and replication: OR  = 0.89, p = 5.35 × 10 ) and rs943126 from pantothenate kinase 1 (PANK1) (discovery: OR  = 0.85, p = 3.10 × 10 and replication: OR  = 0.89, p = 1.30 × 10 ). Both variants regulate gene expression of 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.