A large-scale, consortium-based genomewide association study of asthma.
Susceptibility to asthma is influenced by genes and environment; implicated genes may indicate pathways for therapeutic intervention. Genetic risk factors may be useful in identifying subtypes of asthma and determining whether intermediate phenotypes, such as elevation of the total serum IgE level, are causally linked to disease.



We carried out a genomewide association study by genotyping 10,365 persons with physician-diagnosed asthma and 16,110 unaffected persons, all of whom were matched for ancestry. We used random-effects pooled analysis to test for association in the overall study population and in subgroups of subjects with childhood-onset asthma (defined as asthma developing before 16 years of age), later-onset asthma, severe asthma, and occupational asthma.



We observed associations of genomewide significance between asthma and the following single-nucleotide polymorphisms: rs3771166 on chromosome 2, implicating IL1RL1/IL18R1 (P=3×10(−9)); rs9273349 on chromosome 6, implicating HLA-DQ (P=7×10(−14)); rs1342326 on chromosome 9, flanking IL33 (P=9×10(−10)); rs744910 on chromosome 15 in SMAD3 (P=4×10(−9)); and rs2284033 on chromosome 22 in IL2RB (P=1.1×10(−8)). Association with the ORMDL3/GSDMB locus on chromosome 17q21 was specific to childhood-onset disease (rs2305480, P=6×10(−23)). Only HLA-DR showed a significant genomewide association with the total serum IgE concentration, and loci strongly associated with IgE levels were not associated with asthma.



Asthma is genetically heterogeneous. A few common alleles are associated with disease risk at all ages. Implicated genes suggest a role for communication of epithelial damage to the adaptive immune system and activation of airway inflammation. Variants at the ORMDL3/GSDMB locus are associated only with childhood-onset disease. Elevation of total serum IgE levels has a minor role in the development of asthma. (Funded by the European Commission and others.)
Moffatt
Miriam F
MF
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Gut
Ivo G
IG
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Demenais
Florence
F
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Strachan
David P
DP
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Bouzigon
Emmanuelle
E
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Heath
Simon
S
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
von Mutius
Erika
E
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Farrall
Martin
M
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Lathrop
Mark
M
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
Cookson
William O C M
WOCM
National Heart and Lung Institute, Imperial College (M.F.M., W.O.C.M.C.), the Division of Community Health Sciences, St. George's, University of London (D.P.S.), and Royal Brompton and Harefield NHS Foundation Trust (W.O.C.M.C.) - all in London; Commissariat à l'Energie Atomique, Institut de Génomique, Centre National de Génotypage, Evry, France (I.G.G., S.H., M.L.); INSERM, Unité 946, Fondation Jean-Dausset-Centre d'Etude du Polymorphisme Humain (CEPH) (F.D., E.B.), Fondation Jean Dausset-CEPH (F.D., E.B., M.L.), and Université Paris Diderot Paris 7, Institut Universitaire d'Hématologie (F.D., E.B.) - all in Paris; University Children's Hospital, Asthma and Allergy Department, Ludwig Maximilians University, Munich, Germany (E.M.); and Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom (M.F.).
D000293:Adolescent; D017668:Age of Onset; D001249:Asthma / Q000235:genetics* / Q000276:immunology; D016022:Case-Control Studies; D002648:Child; D002877:Chromosomes, Human; D005260:Female; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D006967:Hypersensitivity / Q000150:complications; D007073:Immunoglobulin E / Q000097:blood*; D016015:Logistic Models; D008297:Male; D009784:Occupational Diseases / Q000235:genetics; D016017:Odds Ratio; D020641:Polymorphism, Single Nucleotide; D018418:Th2 Cells / Q000276:immunology
D006684:HLA-DR Antigens; D007073:Immunoglobulin E