Abstract
Genome-wide association studies followed by replication provide a powerful approach to map genetic risk factors for asthma. We sought to search for new variants associated with asthma and attempt to replicate the association with four loci reported previously (ORMDL3, PDE4D, DENND1B and IL1RL1). Genome-wide association analyses of individual single nucleotide polymorphisms (SNPs), rare copy number variants (CNVs) and overall CNV burden were carried out in 986 asthma cases and 1846 asthma-free controls from Australia. The most-associated locus in the SNP analysis was ORMDL3 (rs6503525, P=4.8 × 10−7). Five other loci were associated with P<10−5, most notably the chemokine CXC motif ligand 14 (CXCL14) gene (rs31263, P=7.8 × 10−6). We found no evidence for association with the specific risk variants reported recently for PDE4D, DENND1B and ILR1L1. However, a variant in IL1RL1 that is in low linkage disequilibrium with that reported previously was associated with asthma risk after accounting for all variants tested (rs10197862, gene wide P=0.01). This association replicated convincingly in an independent cohort (P=2.4 × 10−4). A 300-kb deletion on chromosome 17q21 was associated with asthma risk, but this did not reach experiment-wide significance. Asthma cases and controls had comparable CNV rates, length and number of genes affected by deletions or duplications. In conclusion, we confirm the association between asthma risk and variants in ORMDL3 and identify a novel risk variant in IL1RL1. Follow-up of the 17q21 deletion in larger cohorts is warranted.
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Acknowledgements
We thank the twins and their families for their participation; Dixie Statham, Ann Eldridge, Marlene Grace and Kerrie McAloney for sample collection; Lisa Bowdler and Steven Crooks for DNA processing; David Smyth, Harry Beeby and Daniel Park for IT support. Funding was provided by the Australian National Health and Medical Research Council (241944, 339462, 389927, 389875, 389891, 389892, 389938, 442915, 442981, 496739, 552485, 552498, 613627), the Australian Research Council (A7960034, A79906588, A79801419, DP0770096, DP0212016, DP0343921), the FP-5 GenomEUtwin Project (QLG2-CT-2002-01254) and the US National Institutes of Health (NIH Grants AA07728, AA07535, AA10248, AA11998, AA13320, AA13321, AA13326, AA14041, DA12854, MH66206). A portion of the genotyping on which this study was based (Illumina 370k scans on 4300 individuals) was carried out at the Center for Inherited Disease Research, Baltimore (CIDR) through an access award to our late colleague Dr Richard Todd (Psychiatry, Washington University School of Medicine, St Louis). SEM, DRN, MARF, GWM and PMV are supported by the NHMRC Fellowship Scheme.
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Ferreira, M., McRae, A., Medland, S. et al. Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia. Eur J Hum Genet 19, 458–464 (2011). https://doi.org/10.1038/ejhg.2010.191
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DOI: https://doi.org/10.1038/ejhg.2010.191
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