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A Genome Wide Association Study of Moderate-Severe Asthma in subjects from the United Kingdom

Nick Shrine, Maria Soler-Artigas, Michael Portelli, Neil Bennett, Ioanna Ntalla, Amanda Henry, Charlotte Billington, Dominic Shaw, Zara Pogson, Andrew Fogerty, Trish McKeever, Leon Jonker, Amisha Singapuri, Liam Heaney, Adel Mansur, Rekha Chaudhuri, Neil Thomson, John Holloway, Gabrielle Lockett, Peter Howarth, Ratko Djukanovic, Jenny Hankinson, Richard Niven, Angela Simpson, Kian Chung, Peter Sterk, John Blakey, Ian Adcock, Martin Tobin, Ian Hall, Chris Brightling, Louise Wain, Ian Sayers
European Respiratory Journal 2017 50: PA1815; DOI: 10.1183/1393003.congress-2017.PA1815
Nick Shrine
1University of Leicester, Leicester, United Kingdom
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Maria Soler-Artigas
1University of Leicester, Leicester, United Kingdom
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Michael Portelli
2University of Nottingham, Nottingham, United Kingdom
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Neil Bennett
1University of Leicester, Leicester, United Kingdom
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Ioanna Ntalla
1University of Leicester, Leicester, United Kingdom
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Amanda Henry
2University of Nottingham, Nottingham, United Kingdom
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Charlotte Billington
2University of Nottingham, Nottingham, United Kingdom
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Dominic Shaw
2University of Nottingham, Nottingham, United Kingdom
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Zara Pogson
2University of Nottingham, Nottingham, United Kingdom
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Andrew Fogerty
2University of Nottingham, Nottingham, United Kingdom
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Trish McKeever
2University of Nottingham, Nottingham, United Kingdom
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Leon Jonker
3North Cumbria University Hospitals NHS Trust, Cumbria, United Kingdom
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Amisha Singapuri
1University of Leicester, Leicester, United Kingdom
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Liam Heaney
4University of Belfast, Belfast, United Kingdom
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Adel Mansur
5Birmingham Heartlands Hospital, Birmingham, United Kingdom
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Rekha Chaudhuri
6University of Glasgow, Glasgow, United Kingdom
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Neil Thomson
6University of Glasgow, Glasgow, United Kingdom
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John Holloway
7University of Southampton, Southampton, United Kingdom
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Gabrielle Lockett
7University of Southampton, Southampton, United Kingdom
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Peter Howarth
7University of Southampton, Southampton, United Kingdom
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Ratko Djukanovic
7University of Southampton, Southampton, United Kingdom
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Jenny Hankinson
8University of Manchester, Manchester, United Kingdom
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Richard Niven
8University of Manchester, Manchester, United Kingdom
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Angela Simpson
8University of Manchester, Manchester, United Kingdom
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Kian Chung
9Imperial College, London, United Kingdom
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Peter Sterk
10University of Amsterdam, Amsterdam, Netherlands
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John Blakey
11Liverpool School of Tropical Medicine, Liverpool, United Kingdom
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Ian Adcock
9Imperial College, London, United Kingdom
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Martin Tobin
1University of Leicester, Leicester, United Kingdom
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Ian Hall
2University of Nottingham, Nottingham, United Kingdom
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Chris Brightling
1University of Leicester, Leicester, United Kingdom
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Louise Wain
1University of Leicester, Leicester, United Kingdom
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Ian Sayers
2University of Nottingham, Nottingham, United Kingdom
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Abstract

Rationale: Genome wide association studies (GWAS) in asthma have been successful in identifying disease susceptibility genes, however to date these have focused on mild disease. The genetic risk factors for moderate-severe asthma remain unclear.

Aim: To identify common genetic variants affecting susceptibility to develop moderate-severe asthma.

Methods: We identified asthma cases and controls from UK Biobank and additional cases from the Genetics of Asthma Severity & Phenotypes (GASP) cohort. A genome-wide association study was undertaken in 5,135 European ancestry individuals with moderate-severe asthma based on British Thoracic Society criteria 3 or above and 25,675 controls free from lung disease, allergic rhinitis and atopic dermatitis. After imputation (UK10K + 1000 genomes Phase 3) and standard quality control measures, the association of 33,771,858 single nucleotide polymorphisms (SNPs) were tested. A logistic model of association of asthma status with imputed genotype dose was fitted using SNPTEST adjusted for ancestry principal components.

Results: We identified 22 loci showing association (P < 5 × 10(-8)) including novel signals in or near D2HGDH, STAT6, HLA-B, CD247, GATA3, PDCD1LG2, ZNF652, RPAP3, MUC5AC and BACH2. Previously described asthma loci where replicated including signals in or near HLA-DQB1, TSLP, IL1RL1/IL18R1, CLEC16A, GATA3, IL33, SMAD3, SLC22A5/IL13, C11orf30, ZBTB10, IKZF3-ORMDL3 and IKZF4.

Conclusion: The largest genome-wide association study of moderate-severe asthma to date was carried out and multiple novel loci where identified. These findings may provide new insight into the molecular mechanisms underlying this difficult to treat population.

  • Copyright ©the authors 2017
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A Genome Wide Association Study of Moderate-Severe Asthma in subjects from the United Kingdom
Nick Shrine, Maria Soler-Artigas, Michael Portelli, Neil Bennett, Ioanna Ntalla, Amanda Henry, Charlotte Billington, Dominic Shaw, Zara Pogson, Andrew Fogerty, Trish McKeever, Leon Jonker, Amisha Singapuri, Liam Heaney, Adel Mansur, Rekha Chaudhuri, Neil Thomson, John Holloway, Gabrielle Lockett, Peter Howarth, Ratko Djukanovic, Jenny Hankinson, Richard Niven, Angela Simpson, Kian Chung, Peter Sterk, John Blakey, Ian Adcock, Martin Tobin, Ian Hall, Chris Brightling, Louise Wain, Ian Sayers
European Respiratory Journal Sep 2017, 50 (suppl 61) PA1815; DOI: 10.1183/1393003.congress-2017.PA1815

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A Genome Wide Association Study of Moderate-Severe Asthma in subjects from the United Kingdom
Nick Shrine, Maria Soler-Artigas, Michael Portelli, Neil Bennett, Ioanna Ntalla, Amanda Henry, Charlotte Billington, Dominic Shaw, Zara Pogson, Andrew Fogerty, Trish McKeever, Leon Jonker, Amisha Singapuri, Liam Heaney, Adel Mansur, Rekha Chaudhuri, Neil Thomson, John Holloway, Gabrielle Lockett, Peter Howarth, Ratko Djukanovic, Jenny Hankinson, Richard Niven, Angela Simpson, Kian Chung, Peter Sterk, John Blakey, Ian Adcock, Martin Tobin, Ian Hall, Chris Brightling, Louise Wain, Ian Sayers
European Respiratory Journal Sep 2017, 50 (suppl 61) PA1815; DOI: 10.1183/1393003.congress-2017.PA1815
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