FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

Tarunveer S. Ahluwalia, Anders U. Eliasen, Astrid Sevelsted, Casper-Emil T. Pedersen, Jakob Stokholm, Bo Chawes, Jette Bork-Jensen, Niels Grarup, Oluf Pedersen, Torben Hansen, Allan Linneberg, Amitabh Sharma, Scott T. Weiss, Michael D. Evans, Daniel J. Jackson, Andreanne Morin, Karen A. Krogfelt, Susanne Schjørring, Preben B. Mortensen, David M. Hougaard, Jonas Bybjerg-Grauholm, Marie Bækvad-Hansen, Ole Mors, Merete Nordentoft, Anders D. Børglum, Thomas Werge, Esben Agerbo, James E. Gern, Robert F. Lemanske, Carole Ober, Anders G. Pedersen, Hans Bisgaard and Klaus Bønnelykke ()
Additional contact information
Tarunveer S. Ahluwalia: University of Copenhagen
Anders U. Eliasen: University of Copenhagen
Astrid Sevelsted: University of Copenhagen
Casper-Emil T. Pedersen: University of Copenhagen
Jakob Stokholm: University of Copenhagen
Bo Chawes: University of Copenhagen
Jette Bork-Jensen: University of Copenhagen
Niels Grarup: University of Copenhagen
Oluf Pedersen: University of Copenhagen
Torben Hansen: University of Copenhagen
Allan Linneberg: The Capital Region
Amitabh Sharma: Harvard Medical School
Scott T. Weiss: Harvard Medical School
Michael D. Evans: University of Minnesota
Daniel J. Jackson: University of Wisconsin
Andreanne Morin: University of Chicago
Karen A. Krogfelt: Parasites and Fungi, Statens Serum Institut
Susanne Schjørring: Parasites and Fungi, Statens Serum Institut
Preben B. Mortensen: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
David M. Hougaard: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Jonas Bybjerg-Grauholm: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Marie Bækvad-Hansen: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Ole Mors: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Merete Nordentoft: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Anders D. Børglum: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Thomas Werge: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
Esben Agerbo: The Lundbeck Foundation Initiative for Integrated Psychiatric Research
James E. Gern: University of Wisconsin
Robert F. Lemanske: University of Wisconsin
Carole Ober: University of Chicago
Anders G. Pedersen: Technical University of Denmark
Hans Bisgaard: University of Copenhagen
Klaus Bønnelykke: University of Copenhagen

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-020-19814-6

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