title: Unifying candidate gene and GWAS Approaches in Asthma.
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.
authors.affiliation: Center for Pediatrics, Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Michel
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
authors.forename: Norman
authors.initials: N
authors.lastname: Klopp
authors.forename: Andreas
authors.initials: A
authors.lastname: Ruether
authors.forename: Ashish
authors.initials: A
authors.lastname: Kumar
authors.forename: Michaela
authors.initials: M
authors.lastname: Schedel
authors.forename: Christian
authors.initials: C
authors.lastname: Vogelberg
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.forename: Andrea
authors.initials: A
authors.lastname: von Berg
authors.forename: Albrecht
authors.initials: A
authors.lastname: Bufe
authors.forename: Ernst
authors.initials: E
authors.lastname: Rietschel
authors.forename: Andrea
authors.initials: A
authors.lastname: Heinzmann
authors.forename: Otto
authors.initials: O
authors.lastname: Laub
authors.forename: Burkhard
authors.initials: B
authors.lastname: Simma
authors.forename: Thomas
authors.initials: T
authors.lastname: Frischer
authors.forename: Jon
authors.initials: J
authors.lastname: Genuneit
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.forename: Stefan
authors.initials: S
authors.lastname: Schreiber
authors.forename: Mark
authors.initials: M
authors.lastname: Lathrop
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
mesh_terms: D000293:Adolescent; D000483:Alleles; D001249:Asthma / Q000235:genetics*; D002648:Child; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases / Q000235:genetics; D019332:Endothelin-1 / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods*; D005838:Genotype; D051549:Glutathione S-Transferase pi / Q000235:genetics; D006801:Humans; D053762:Interleukin-12 Subunit p40 / Q000235:genetics; D018793:Interleukin-13 / Q000235:genetics; D015847:Interleukin-4 / Q000235:genetics; D053662:Interleukin-4 Receptor alpha Subunit / Q000235:genetics; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D020641:Polymorphism, Single Nucleotide; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
chemical_list: D019332:Endothelin-1; C500879:IL12B protein, human; C504000:IL4R protein, human; D053762:Interleukin-12 Subunit p40; D018793:Interleukin-13; D053662:Interleukin-4 Receptor alpha Subunit; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; C439524:TNF protein, human; D014409:Tumor Necrosis Factor-alpha; D015847:Interleukin-4; C496556:GSTP1 protein, human; D051549:Glutathione S-Transferase pi; C476879:DPP10 protein, human; D004152:Dipeptidyl-Peptidases and Tripeptidyl-Peptidases