title: Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.
abstract: Asthma is caused by a combination of poorly understood genetic and environmental factors. We have systematically mapped the effects of single nucleotide polymorphisms (SNPs) on the presence of childhood onset asthma by genome-wide association. We characterized more than 317,000 SNPs in DNA from 994 patients with childhood onset asthma and 1,243 non-asthmatics, using family and case-referent panels. Here we show multiple markers on chromosome 17q21 to be strongly and reproducibly associated with childhood onset asthma in family and case-referent panels with a combined P value of P < 10(-12). In independent replication studies the 17q21 locus showed strong association with diagnosis of childhood asthma in 2,320 subjects from a cohort of German children (P = 0.0003) and in 3,301 subjects from the British 1958 Birth Cohort (P = 0.0005). We systematically evaluated the relationships between markers of the 17q21 locus and transcript levels of genes in Epstein-Barr virus (EBV)-transformed lymphoblastoid cell lines from children in the asthma family panel used in our association study. The SNPs associated with childhood asthma were consistently and strongly associated (P < 10(-22)) in cis with transcript levels of ORMDL3, a member of a gene family that encodes transmembrane proteins anchored in the endoplasmic reticulum. The results indicate that genetic variants regulating ORMDL3 expression are determinants of susceptibility to childhood asthma.
authors.affiliation: National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
authors.forename: Miriam F
authors.initials: MF
authors.lastname: Moffatt
authors.forename: Michael
authors.initials: M
authors.lastname: Kabesch
authors.forename: Liming
authors.initials: L
authors.lastname: Liang
authors.forename: Anna L
authors.initials: AL
authors.lastname: Dixon
authors.forename: David
authors.initials: D
authors.lastname: Strachan
authors.forename: Simon
authors.initials: S
authors.lastname: Heath
authors.forename: Martin
authors.initials: M
authors.lastname: Depner
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: Burkard
authors.initials: B
authors.lastname: Simma
authors.forename: Thomas
authors.initials: T
authors.lastname: Frischer
authors.forename: Saffron A G
authors.initials: SA
authors.lastname: Willis-Owen
authors.forename: Kenny C C
authors.initials: KC
authors.lastname: Wong
authors.forename: Thomas
authors.initials: T
authors.lastname: Illig
authors.forename: Christian
authors.initials: C
authors.lastname: Vogelberg
authors.forename: Stephan K
authors.initials: SK
authors.lastname: Weiland
authors.forename: Erika
authors.initials: E
authors.lastname: von Mutius
authors.forename: Gonçalo R
authors.initials: GR
authors.lastname: Abecasis
authors.forename: Martin
authors.initials: M
authors.lastname: Farrall
authors.forename: Ivo G
authors.initials: IG
authors.lastname: Gut
authors.forename: G Mark
authors.initials: GM
authors.lastname: Lathrop
authors.forename: William O C
authors.initials: WO
authors.lastname: Cookson
mesh_terms: D017668:Age of Onset; D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002886:Chromosomes, Human, Pair 17 / Q000235:genetics; D005786:Gene Expression Regulation / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005858:Germany; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D006113:United Kingdom
chemical_list: D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D012333:RNA, Messenger