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; Klaus Bønnelykke

doi:10.1038/s41467-020-19814-6

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, Klaus Bønnelykke^*

^*Corresponding author for this work

University of Copenhagen
Harvard University
University of Minnesota Twin Cities
University of Wisconsin-Madison
The University of Chicago
Roskilde University
Statens Serum Institut
Aarhus University

Research output: Contribution to journal › Journal article › Research › peer-review

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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), P_discovery = 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.

Original language	English
Article number	6398
Journal	Nature Communications
Volume	11
Issue number	1
Number of pages	12
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-020-19814-6
Publication status	Published - 2020

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Ahluwalia, T. S., Eliasen, A. U., Sevelsted, A., Pedersen, C. E. T., Stokholm, J., Chawes, B., Bork-Jensen, J., Grarup, N., Pedersen, O., Hansen, T., Linneberg, A., Sharma, A., Weiss, S. T., Evans, M. D., Jackson, D. J., Morin, A., Krogfelt, K. A., Schjørring, S., Mortensen, P. B., ... Bønnelykke, K. (2020). FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses. Nature Communications, 11(1), Article 6398. https://doi.org/10.1038/s41467-020-19814-6

@article{0c5ef97107054ae7bf5be77221f1b408,

title = "FUT2{\textendash}ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses",

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{\textendash}1.25), Pdiscovery = 2.6 {\texttimes} 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.",

author = "Ahluwalia, \{Tarunveer S.\} and Eliasen, \{Anders U.\} and Astrid Sevelsted and Pedersen, \{Casper Emil T.\} and Jakob Stokholm and Bo Chawes and Jette Bork-Jensen and Niels Grarup and Oluf Pedersen and Torben Hansen and Allan Linneberg and Amitabh Sharma and Weiss, \{Scott T.\} and Evans, \{Michael D.\} and Jackson, \{Daniel J.\} and Andreanne Morin and Krogfelt, \{Karen A.\} and Susanne Schj{\o}rring and Mortensen, \{Preben B.\} and Hougaard, \{David M.\} and Jonas Bybjerg-Grauholm and Marie B{\ae}kvad-Hansen and Ole Mors and Merete Nordentoft and B{\o}rglum, \{Anders D.\} and Thomas Werge and Esben Agerbo and Gern, \{James E.\} and Lemanske, \{Robert F.\} and Carole Ober and Pedersen, \{Anders G.\} and Hans Bisgaard and Klaus B{\o}nnelykke",

year = "2020",

doi = "10.1038/s41467-020-19814-6",

language = "English",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

number = "1",

}

Ahluwalia, TS, Eliasen, AU, Sevelsted, A, Pedersen, CET, Stokholm, J, Chawes, B, Bork-Jensen, J, Grarup, N, Pedersen, O, Hansen, T, Linneberg, A, Sharma, A, Weiss, ST, Evans, MD, Jackson, DJ, Morin, A, Krogfelt, KA, Schjørring, S, Mortensen, PB, Hougaard, DM, Bybjerg-Grauholm, J, Bækvad-Hansen, M, Mors, O, Nordentoft, M, Børglum, AD, Werge, T, Agerbo, E, Gern, JE, Lemanske, RF, Ober, C, Pedersen, AG, Bisgaard, H & Bønnelykke, K 2020, 'FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses', Nature Communications, vol. 11, no. 1, 6398. https://doi.org/10.1038/s41467-020-19814-6

TY - JOUR

T1 - FUT2–ABO epistasis increases the risk of early childhood asthma and Streptococcus pneumoniae respiratory illnesses

AU - Ahluwalia, Tarunveer S.

AU - Eliasen, Anders U.

AU - Sevelsted, Astrid

AU - Pedersen, Casper Emil T.

AU - Stokholm, Jakob

AU - Chawes, Bo

AU - Bork-Jensen, Jette

AU - Grarup, Niels

AU - Pedersen, Oluf

AU - Hansen, Torben

AU - Linneberg, Allan

AU - Sharma, Amitabh

AU - Weiss, Scott T.

AU - Evans, Michael D.

AU - Jackson, Daniel J.

AU - Morin, Andreanne

AU - Krogfelt, Karen A.

AU - Schjørring, Susanne

AU - Mortensen, Preben B.

AU - Hougaard, David M.

AU - Bybjerg-Grauholm, Jonas

AU - Bækvad-Hansen, Marie

AU - Mors, Ole

AU - Nordentoft, Merete

AU - Børglum, Anders D.

AU - Werge, Thomas

AU - Agerbo, Esben

AU - Gern, James E.

AU - Lemanske, Robert F.

AU - Ober, Carole

AU - Pedersen, Anders G.

AU - Bisgaard, Hans

AU - Bønnelykke, Klaus

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

U2 - 10.1038/s41467-020-19814-6

DO - 10.1038/s41467-020-19814-6

M3 - Journal article

C2 - 33328473

AN - SCOPUS:85097613852

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 6398

ER -

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

Abstract

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