| Title: |
Moderate-to-severe asthma in individuals of European ancestry: a genome-wide association study |
| Authors: |
Shrine, N; Portelli, MA; John, C; Soler Artigas, M; Bennett, N; Hall, R; Lewis, J; Henry, AP; Billington, CK; Ahmad, A; Packer, RJ; Shaw, D; Pogson, ZEK; Fogarty, A; McKeever, TM; Singapuri, A; Heaney, LG; Mansur, AH; Chaudhuri, R; Thomson, NC; Holloway, JW; Lockett, GA; Howarth, PH; Djukanovic, R; Hankinson, J; Niven, R; Simpson, A; Chung, KF; Sterk, PJ; Blakey, JD; Adcock, IM; Hu, S; Guo, Y; Obeidat, M; Sin, DD; Van den Berge, M; Nickle, DC; Bossé, Y; Tobin, MD; Hall, IP; Brightling, CE; Wain, LV; Sayers, I |
| Contributors: |
Commission of the European Communities; National Institute for Health Research |
| Source: |
34 ; 20 |
| Publisher Information: |
Elsevier |
| Publication Year: |
2018 |
| Collection: |
Imperial College London: Spiral |
| Subject Terms: |
Science & Technology; Life Sciences & Biomedicine; Critical Care Medicine; Respiratory System; General & Internal Medicine; RISK LOCI; SUSCEPTIBILITY LOCI; ALLERGIC DISEASE; HAY-FEVER; VARIANTS; METAANALYSIS; LUNG; IDENTIFICATION; EXPRESSION; BLOOD; Adult; Aged; Asthma; Case-Control Studies; European Continental Ancestry Group; Female; GATA3 Transcription Factor; Genetic Predisposition to Disease; Genome-Wide Association Study; Genotype; Humans; Male; Middle Aged; Mucin 5AC; Proteins |
| Subject Geographic: |
England |
| Description: |
BACKGROUND: Few genetic studies that focus on moderate-to-severe asthma exist. We aimed to identity novel genetic variants associated with moderate-to-severe asthma, see whether previously identified genetic variants for all types of asthma contribute to moderate-to-severe asthma, and provide novel mechanistic insights using expression analyses in patients with asthma. METHODS: In this genome-wide association study, we used a two-stage case-control design. In stage 1, we genotyped patient-level data from two UK cohorts (the Genetics of Asthma Severity and Phenotypes [GASP] initiative and the Unbiased BIOmarkers in PREDiction of respiratory disease outcomes [U-BIOPRED] project) and used data from the UK Biobank to collect patient-level genomic data for cases and controls of European ancestry in a 1:5 ratio. Cases were defined as having moderate-to-severe asthma if they were taking appropriate medication or had been diagnosed by a doctor. Controls were defined as not having asthma, rhinitis, eczema, allergy, emphysema, or chronic bronchitis as diagnosed by a doctor. For stage 2, an independent cohort of cases and controls (1:5) was selected from the UK Biobank only, with no overlap with stage 1 samples. In stage 1 we undertook a genome-wide association study of moderate-to-severe asthma, and in stage 2 we followed up independent variants that reached the significance threshold of p less than 1 × 10-6 in stage 1. We set genome-wide significance at p less than 5 × 10-8. For novel signals, we investigated their effect on all types of asthma (mild, moderate, and severe). For all signals meeting genome-wide significance, we investigated their effect on gene expression in patients with asthma and controls. FINDINGS: We included 5135 cases and 25 675 controls for stage 1, and 5414 cases and 21 471 controls for stage 2. We identified 24 genome-wide significant signals of association with moderate-to-severe asthma, including several signals in innate or adaptive immune-response genes. Three novel signals were identified: ... |
| Document Type: |
article in journal/newspaper |
| Language: |
English |
| Relation: |
Lancet Respiratory Medicine; http://hdl.handle.net/10044/1/65188; 115010 |
| DOI: |
10.1016/S2213-2600(18)30389-8 |
| Availability: |
http://hdl.handle.net/10044/1/65188; https://doi.org/10.1016/S2213-2600(18)30389-8 |
| Rights: |
© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/) |
| Accession Number: |
edsbas.66CE2BE9 |
| Database: |
BASE |