title: Association between ORMDL3, IL1RL1 and a deletion on chromosome 17q21 with asthma risk in Australia.
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.
authors.affiliation: Queensland Institute of Medical Research, Brisbane, QLD, Australia. manuel.ferreira@qimr.edu.au
authors.forename: Manuel A R
authors.initials: MA
authors.lastname: Ferreira
authors.forename: Allan F
authors.initials: AF
authors.lastname: McRae
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Medland
authors.forename: Dale R
authors.initials: DR
authors.lastname: Nyholt
authors.forename: Scott D
authors.initials: SD
authors.lastname: Gordon
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: Wright
authors.forename: Anjali K
authors.initials: AK
authors.lastname: Henders
authors.forename: Pamela A
authors.initials: PA
authors.lastname: Madden
authors.forename: Peter M
authors.initials: PM
authors.lastname: Visscher
authors.forename: Naomi R
authors.initials: NR
authors.lastname: Wray
authors.forename: Andrew C
authors.initials: AC
authors.lastname: Heath
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.forename: David L
authors.initials: DL
authors.lastname: Duffy
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
mesh_terms: D001249:Asthma / Q000453:epidemiology* / Q000235:genetics*; D001315:Australia / Q000453:epidemiology; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D056915:DNA Copy Number Variations; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics
chemical_list: C079241:IL1RL1 protein, human; D000072179:Interleukin-1 Receptor-Like 1 Protein; D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D011956:Receptors, Cell Surface; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human