1. National Heart and Lung Institute, Imperial College, London SW3 6LY, UK
2. University Children's Hospital, Ludwig Maximilians University, D80337 Munich, Germany
3. Center for Statistical Genetics, Department of Biostatistics, SPH II, Ann Arbor, Michigan 48109-2029, USA
4. Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK
5. Division of Community Health Science, St George's, University of London, London SW17 0RE, UK
6. Centre National de Génotypage, Institut Génomique, Commissariat à l'Énergie Atomique, 91057 Evry, France
7. Research Institute for the Prevention of Allergic Diseases, Children's Department, Marien-Hospital, D46483 Wesel, Germany
8. Department of Experimental Pneumology, Ruhr-University, D44789 Bochum, Germany
9. University Children's Hospital, University of Cologne, D50924 Cologne, Germany
10. University Children's Hospital, Albert Ludwigs University, D79106 Freiburg, Germany
11. Children's Department, Feldkirch Hospital, A6800 Feldkirch, Austria
12. University Children's Hospital Vienna, A1090 Vienna, Austria
13. Institute of Epidemiology, GSF-Research Centre for Environment and Health, D85764 Neuherberg, Germany
14. University Children's Hospital, Technical University Dresden, D01307 Dresden, Germany
15. Institute of Epidemiology, Ulm University, D89081 Germany
16. These authors contributed equally to this work.

Correspondence to: William O. C. Cookson¹ Correspondence and requests for materials should be addressed to W.O.C.C. (Email: w.cookson@imperial.ac.uk).

Asthma is caused by a combination of poorly understood genetic and environmental factors^{1, 2}. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10^-12. In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein–Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10^-22) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum³. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.

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