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RESEARCH ARTICLE
Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA
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1 Respiratory Epidemiology and Public Health, Imperial College London, London, United Kingdom, 2 Department of Epidemiology and Biostatistics, Imperial College London, London, United Kingdom, 3 Department of Medical and Molecular Genetics, King’s College London, London, United Kingdom, 4 Department of Chronic Disease Prevention, National Institute for Health and Welfare, Helsinki, Finland, 5 Divisions of Genetics and Endocrinology, Children’s Hospital, Boston, Massachusetts, United States of America, 6 Broad Institute, Cambridge, Massachusetts, United States of America, 7 The Queensland Institute of Medical Research, Brisbane, Australia, 8 Division of Community Health Sciences, St George’s, University of London, London, United Kingdom, 9 MRC Epidemiology Unit, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge, United Kingdom, 10 Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia,, 11 University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Australia, 12 Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia, 13 Skin and Allergy Hospital, Helsinki University Hospital, Helsinki, Finland, 14 Washington University School of Medicine, St. Louis, Missouri, United States of America, 15 Department of Medical Sciences: Respiratory Medicine and Allergology, Uppsala University, Uppsala, Sweden, 16Department of Clinical Physiology, Tampere University Hospital, Tampere, Finland, 17 Clinical Gerontology Unit, Addenbrooke’s Hospital, Cambridge, United Kingdom, 18 Finnish Institute of Occupational Health, Oulu, Finland, 19 School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Perth, Australia, 20 Department of Clinical Chemistry, University of Tampere and Tampere University Hospital, Tampere, Finland, 21 Woolcock Institute of Medical Research, University of Sydney, Sydney, Australia, 22 Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, United Kingdom, 23 Institute for Molecular Medicine Finland, University of Helsinki, Helsinki, Finland, 24 Medical and Population Genetics and Genetic Analysis Platform, The Broad Institute of MIT and Harvard, Cambridge, Massachusetts, United States of America, 25 Department of Medical Genetics, University of Helsinki and University Central Hospital, Helsinki, Finland, 26 Department of Children, Young People and Families, National Institute for Health and Welfare, Helsinki, Finland,27 Institute of Clinical Medicine/Obstetrics and Gynecology, University of Oulu, Oulu, Finland, 28 Respiratory Medicine, Murdoch Children’s Research Institute, Melbourne, Australia, 29 Department of Medicine, University of Turku, Turku, Finland,30 Helmholtz Zentrum Munchen German Research Center for Environmental Health, Munich-Neuherberg, Germany, 31 MRC Health Protection Agency (HPA) Centre for Environment and Health, Imperial College London, London, United Kingdom, 32Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, Australia, 33 National Institute for Health and Welfare, Helsinki, Finland, 34 Unit of General Practice, Helsinki University Central Hospital, Helsinki, Finland, 35 Department of General Practice and Primary Health Care, University of Helsinki, Helsinki, Finland, 36 Folkhälsan Research Center, Helsinki, Finland, 37 Department of Pulmonary Diseases and Clinical Allergology, Turku University Hospital, Turku, Finland, 38 University of Turku, Turku, Finland, 39 Department of Environmental Health, National Institute for Health and Welfare (THL), Kuopio, Finland, 40 Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland, 41 Research Centre of Applied and Preventive Medicine, University of Turku, Turku, Finland, 42 Department of Clinical Physiology, Turku University Hospital, Turku, Finland, 43Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America, 44 The National Heart, Lung, and Blood Institute’s Framingham Heart Study, Framingham, Massachusetts, United States of America, 45 Institute of Health Sciences, University of Oulu, Oulu, Finland, 46 Biocenter Oulu, University of Oulu, Oulu, Finland, 47 Department of Genetics, Harvard Medical School, Boston, Massachusetts, United States of America
Abstract Top
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 sup="sup">−8
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 = 2.4×10−9). 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.
Citation: Ramasamy A, Kuokkanen M, Vedantam S, Gajdos ZK, Couto Alves A, et al. (2012) Genome-Wide Association Studies of Asthma in Population-Based Cohorts Confirm Known and Suggested Loci and Identify an Additional Association near HLA. PLoS ONE 7(9): e44008. doi:10.1371/journal.pone.0044008
Editor: John RB. Perry, Peninsula College of Medicine and Dentistry, United Kingdom
Received: April 24, 2012; Accepted: July 27, 2012; Published: September 28, 2012
Copyright: © 2012 Ramasamy et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: Please see Supplementary Methods S1 for the details of the many charities, governmental bodies and scientific funding organisations that supported the study recruitment, phenotyping, DNA collection and genotyping for the studies involved in the discovery stage (Stage1) and replication stage (Stage2). The personal research funding supports are listed as follows: AR was supported through the European Commission (through project GABRIEL – contract #018996 under the Integrated Program LSH-2004-1.2.5-1) and the Department of Health, UK. ACA was funded by the European Commission, Framework 7 (grant #223367). The National Health and Medical Research Council, Australia (NHMRC) supported MARF through a project grant (#613627), MAB via a Principal Research Fellowship (#455836) and SCD, DLD, NGM, MCM and GWM via a fellowship scheme. AP acknowledges funding from The Academy of Finland Center of Excellence in Complex Disease Genetics (#213506 and 129680), the Wellcome Trust (#089062), the European Community’s Framework 7 Programme and the ENGAGE Consortium (#201413). The Academy of Finland supported EW (#129287, #134839) and VS (#129494, #139635). JE was supported through Academy of Finland, Samfundet Folkhälsan, Finnish Diabetes Research Foundation, Finska Läkaresällskapet, Finnish Foundation for Cardiovascular Research; Yrjö Jahnsson Foundation and Foundation Liv och Hälsa. TL was supported by Foundation of the Finnish Anti-Tuberculosis and Allergy Associations. M-RJ has received financial support from the Academy of Finland, Biocenter Oulu, University of Oulu and National Heart Lung and Blood Institute (NHLBI) – National Institutes of Health (#5R01HL087679-02 through the STAMPEED program 1RL1MH083268-01). JNH was supported by a grant from the American Asthma Foundation for analysis of Framingham SHARe data for association with asthma. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
* E-mail: joelh@broadinstitute.org (JNH); m.jarvelin@imperial.ac.uk (M-RJ); veikko.salomaa@thl.fi (VS)
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