Genetic variants regulating ORMDL3 expression contribute to the risk of childhood asthma.
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.
Moffatt
Miriam F
MF
National Heart and Lung Institute, Imperial College, London SW3 6LY, UK.
Kabesch
Michael
M
Liang
Liming
L
Dixon
Anna L
AL
Strachan
David
D
Heath
Simon
S
Depner
Martin
M
von Berg
Andrea
A
Bufe
Albrecht
A
Rietschel
Ernst
E
Heinzmann
Andrea
A
Simma
Burkard
B
Frischer
Thomas
T
Willis-Owen
Saffron A G
SA
Wong
Kenny C C
KC
Illig
Thomas
T
Vogelberg
Christian
C
Weiland
Stephan K
SK
von Mutius
Erika
E
Abecasis
Gonçalo R
GR
Farrall
Martin
M
Gut
Ivo G
IG
Lathrop
G Mark
GM
Cookson
William O C
WO
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
D008565:Membrane Proteins; C464399:ORMDL3 protein, human; D012333:RNA, Messenger