title: Analyses of associations with asthma in four asthma population samples from Canada and Australia.
abstract: Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca/.
authors.affiliation: James Hogg iCAPTURE Center, University of British Columbia (UBC), 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada.
authors.forename: Denise
authors.initials: D
authors.lastname: Daley
authors.forename: Mathieu
authors.initials: M
authors.lastname: Lemire
authors.forename: Loubna
authors.initials: L
authors.lastname: Akhabir
authors.forename: Moira
authors.initials: M
authors.lastname: Chan-Yeung
authors.forename: Jian Qing
authors.initials: JQ
authors.lastname: He
authors.forename: Treena
authors.initials: T
authors.lastname: McDonald
authors.forename: Andrew
authors.initials: A
authors.lastname: Sandford
authors.forename: Dorota
authors.initials: D
authors.lastname: Stefanowicz
authors.forename: Ben
authors.initials: B
authors.lastname: Tripp
authors.forename: David
authors.initials: D
authors.lastname: Zamar
authors.forename: Yohan
authors.initials: Y
authors.lastname: Bosse
authors.forename: Vincent
authors.initials: V
authors.lastname: Ferretti
authors.forename: Alexandre
authors.initials: A
authors.lastname: Montpetit
authors.forename: Marie-Catherine
authors.initials: MC
authors.lastname: Tessier
authors.forename: Allan
authors.initials: A
authors.lastname: Becker
authors.forename: Anita L
authors.initials: AL
authors.lastname: Kozyrskyj
authors.forename: John
authors.initials: J
authors.lastname: Beilby
authors.forename: Pamela A
authors.initials: PA
authors.lastname: McCaskie
authors.forename: Bill
authors.initials: B
authors.lastname: Musk
authors.forename: Nicole
authors.initials: N
authors.lastname: Warrington
authors.forename: Alan
authors.initials: A
authors.lastname: James
authors.forename: Catherine
authors.initials: C
authors.lastname: Laprise
authors.forename: Lyle J
authors.initials: LJ
authors.lastname: Palmer
authors.forename: Peter D
authors.initials: PD
authors.lastname: Paré
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
mesh_terms: D000483:Alleles; D001249:Asthma / Q000235:genetics*; D001315:Australia; D016535:Bronchial Hyperreactivity / Q000235:genetics; D002170:Canada; D016022:Case-Control Studies; D005190:Family; D005260:Female; D005787:Gene Frequency; D005828:Genetics, Population; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000235:genetics; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide