Asthma is caused by a combination of poorly understood genetic and environmental factors1,2. 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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The study was funded by the Wellcome Trust, the Medical Research Council, the French Ministry of Higher Education and Research, the German Ministry of education and research (BMBF), the national genome research network (NGFN), the National Institutes of Health (NHGRI and NHLBI; G.R.A.), and the European Commission as part of GABRIEL (a multidisciplinary study to identify the genetic and environmental causes of asthma in the European Community). We acknowledge use of genotype data from the British 1958 Birth Cohort DNA collection, funded by the Medical Research Council and the Wellcome Trust. We thank J. Todd for genotyping rs3894194 in the 1958 British Birth cohort.
Microarray and chromosome 17 genotyping data have been deposited in the GEO database, with accession number GSE8052.
Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.
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Moffatt, M., Kabesch, M., Liang, L. et al. Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma. Nature 448, 470–473 (2007). https://doi.org/10.1038/nature06014
ORMDL3/GSDMB genotype as a risk factor for early-onset adult asthma is linked to total serum IgE levels but not to allergic sensitization
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