期刊
PLOS ONE
卷 7, 期 9, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0044008
关键词
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资金
- European Commission [018996, LSH-2004-1.2.5-1, 223367]
- Department of Health, UK
- National Health and Medical Research Council, Australia (NHMRC) [613627, 455836]
- Academy of Finland Center of Excellence in Complex Disease Genetics [213506, 129680]
- Wellcome Trust [089062]
- European Community
- ENGAGE Consortium [201413]
- Academy of Finland [129287, 134839, 129494, 139635]
- Samfundet Folkhalsan
- Finnish Diabetes Research Foundation
- Finska Lakaresallskapet
- Finnish Foundation for Cardiovascular Research
- Yrjo Jahnsson Foundation
- Foundation Liv och Halsa
- Foundation of the Finnish Anti-Tuberculosis Association
- Foundation of the Allergy Association
- Biocenter Oulu, University of Oulu
- National Heart Lung and Blood Institute (NHLBI) - National Institutes of Health [5R01HL087679-02, 1RL1MH083268-01]
- American Asthma Foundation
- Academy of Finland (AKA) [134839, 129287, 134839, 129287] Funding Source: Academy of Finland (AKA)
- Medical Research Council [MC_U106179471, G0401527, G0901214, G0801056B, G1000143] Funding Source: researchfish
- MRC [G0901214] Funding Source: UKRI
Rationale: Asthma has substantial morbidity and mortality and a strong genetic component, but identification of genetic risk factors is limited by availability of suitable studies. Objectives: To test if population-based cohorts with self-reported physician-diagnosed asthma and genome-wide association (GWA) data could be used to validate known associations with asthma and identify novel associations. Methods: The APCAT (Analysis in Population-based Cohorts of Asthma Traits) consortium consists of 1,716 individuals with asthma and 16,888 healthy controls from six European-descent population-based cohorts. We examined associations in APCAT of thirteen variants previously reported as genome-wide significant (P < 5x10(-8)) and three variants reported as suggestive (P < 5 x 10(-7)). We also searched for novel associations in APCAT (Stage 1) and followed-up the most promising variants in 4,035 asthmatics and 11,251 healthy controls (Stage 2). Finally, we conducted the first genome-wide screen for interactions with smoking or hay fever. Main Results: We observed association in the same direction for all thirteen previously reported variants and nominally replicated ten of them. One variant that was previously suggestive, rs11071559 in RORA, now reaches genome-wide significance when combined with our data (P = 2.4x10(-9)). We also identified two genome-wide significant associations: rs13408661 near IL1RL1/IL18R1 (PStage1+Stage2 = 1.1x10(-9)), which is correlated with a variant recently shown to be associated with asthma (rs3771180), and rs9268516 in the HLA region (PStage1+Stage2 = 1.1x10(-8)), which appears to be independent of previously reported associations in this locus. Finally, we found no strong evidence for gene-environment interactions with smoking or hay fever status. Conclusions: Population-based cohorts with simple asthma phenotypes represent a valuable and largely untapped resource for genetic studies of asthma.
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