Asthma with severe exacerbation is the most common cause of hospitalization among young children. We aim to increase the understanding of this clinically important disease entity through a genome-wide association study. The discovery analysis comprises 2866 children experiencing severe asthma exacerbation between ages 2 and 6 years, and 65,415 non-asthmatic controls, and we replicate findings in 918 children from the Copenhagen Prospective Studies on Asthma in Childhood (COPSAC) birth cohorts. We identify rs281379 near FUT2/MAMSTR on chromosome 19 as a novel risk locus (OR = 1.18 (95% CI = 1.11–1.25), Pdiscovery = 2.6 × 10−9) as well as a biologically plausible interaction between functional variants in FUT2 and ABO. We further discover and replicate a potential causal mechanism behind this interaction related to S. pneumoniae respiratory illnesses. These results suggest a novel mechanism of early childhood asthma and demonstrates the importance of phenotype-specificity for discovery of asthma genes and epistasis.
Bibliographical noteFunding Information:
We express our deepest gratitude to the children and families of the COPSAC2000, COPSAC2010, and COPSACsevere cohort studies for all their support and commitment. We acknowledge and appreciate the unique efforts of the COPSAC research team. All funding received by COPSAC is listed on www.copsac.com. The Lundbeck Foundation (Grant no. R16-A1694); The Ministry of Health (Grant no. 903516); Danish Council for Strategic Research (Grant no. 0603-00280B), and The Capital Region Research Foundation have provided core support to the COPSAC research center. T.S.A. was also supported by Steno Diabetes Center Copenhagen, Gentofte, Denmark and the Novo Nordisk Foundation (NNF18OC0052457). The iPSYCH project is funded by the Lundbeck Foundation (Grant nos R102-A9118 and R155-2014-1724) and the universities and university hospitals of Aarhus and Copenhagen. The Danish National Biobank resource was supported by the Novo Nordisk Foundation. No honorarium, grant, or other forms of payment was given to any of the authors to produce this manuscript. The funding agencies did not have any role in the design and conduct of the study; collection, management, and interpretation of the data; or preparation, review, or approval of the manuscript. No pharmaceutical company was involved in the study.
© 2020, The Author(s).
PubMed: MeSH publication types
- Journal Article
- Research Support, Non-U.S. Gov't