Unifying candidate gene and GWAS Approaches in Asthma.

Authors:
Sven Michel, Liming Liang, Martin Depner, Norman Klopp, Andreas Ruether, Ashish Kumar, Michaela Schedel, Christian Vogelberg, Erika von Mutius, Andrea von Berg, Albrecht Bufe, Ernst Rietschel, Andrea Heinzmann, Otto Laub, Burkhard Simma, Thomas Frischer, Jon Genuneit, Ivo G Gut, Stefan Schreiber, Mark Lathrop, Thomas Illig, Michael Kabesch
Year of publication:
2010
Volume:
5
Issue:
11
Issn:
1932-6203
Journal title abbreviated:
PLoS ONE
Journal title long:
PloS one
Impact factor:
2.806
Abstract:
The first genome wide association study (GWAS) for childhood asthma identified a novel major susceptibility locus on chromosome 17q21 harboring the ORMDL3 gene, but the role of previous asthma candidate genes was not specifically analyzed in this GWAS. We systematically identified 89 SNPs in 14 candidate genes previously associated with asthma in >3 independent study populations. We re-genotyped 39 SNPs in these genes not covered by GWAS performed in 703 asthmatics and 658 reference children. Genotyping data were compared to imputation data derived from Illumina HumanHap300 chip genotyping. Results were combined to analyze 566 SNPs covering all 14 candidate gene loci. Genotyped polymorphisms in ADAM33, GSTP1 and VDR showed effects with p-values <0.0035 (corrected for multiple testing). Combining genotyping and imputation, polymorphisms in DPP10, EDN1, IL12B, IL13, IL4, IL4R and TNF showed associations at a significance level between p = 0.05 and p = 0.0035. These data indicate that (a) GWAS coverage is insufficient for many asthma candidate genes, (b) imputation based on these data is reliable but incomplete, and (c) SNPs in three previously identified asthma candidate genes replicate in our GWAS population with significance after correction for multiple testing in 14 genes.