Genome-wide association study of the age of onset of childhood asthma

Erick Forno,Jessica Lasky-Su,Blanca Himes,Judie Howrylak,Clare Ramsey,John Brehm,Barbara Klanderman,John Ziniti,Erik Melén,Goran Pershagen,Magnus Wickman,Fernando Martinez,Dave Mauger,Christine Sorkness,Kelan Tantisira,Benjamin A Raby,Scott T Weiss,Juan C Celedón

doi:10.1016/j.jaci.2012.03.020

Abstract

Childhood asthma is a complex disease with known heritability and phenotypic diversity. Although an earlier onset has been associated with more severe disease, there has been no genome-wide association study of the age of onset of asthma in children. We sought to identify genetic variants associated with earlier onset of childhood asthma. We conducted the first genome-wide association study of the age of onset of childhood asthma among participants in the Childhood Asthma Management Program (CAMP) and used 3 independent cohorts from North America, Costa Rica, and Sweden for replication. Two single nucleotide polymorphisms (SNPs) were associated with earlier onset of asthma in the combined analysis of CAMP and the replication cohorts: rs9815663 (Fisher P= 2.31 × 10(-8)) and rs7927044 (P= 6.54 × 10(-9)). Of these 2 SNPs, rs9815663 was also significantly associated with earlier asthma onset in an analysis including only the replication cohorts. Ten SNPs in linkage disequilibrium with rs9815663 were also associated with earlier asthma onset (2.24 × 10(-7) <P< 8.22 × 10(-6)). Having 1 or more risk alleles of the 2 SNPs of interest (rs9815663 and rs7927044) was associated with lower lung function and higher asthma medication use during 4 years of follow-up in CAMP. We have identified 2 SNPs associated with earlier onset of childhood asthma in 4 independent cohorts.

Highlights

Asthma is a complex disease affecting approximately 7 million children in the United States [1]
We have identified two SNPs associated with earlier onset of childhood asthma in four independent cohorts
We present the results of a genome-wide association studies (GWAS) of the age of onset of asthma in a cohort of North American children enrolled in the Childhood Asthma Management Program (CAMP), followed by replication studies in three independent cohorts of asthmatic children from Latin America, North America, and Europe

Summary

Introduction

Asthma is a complex disease affecting approximately 7 million children in the United States [1]. Variants in more than 40 genes have been associated with asthma [2,3] Of these potential asthma susceptibility genes, a handful (e.g., ORMDL3, PDE4D, DENND1B) have been identified by genome-wide association studies (GWAS)(4–7). The age of onset of asthma has important phenotypic and prognostic implications [9,10], and an earlier age of onset is associated with increased severity of asthma in children with symptoms persisting into school age and adolescence [11,12]. Childhood asthma is a complex disease with known heritability and phenotypic diversity. An earlier onset has been associated with more severe disease, there has been no genome-wide association study of the age of onset of asthma in children. OBJECTIVE—To identify genetic variants associated with earlier onset of childhood asthma

Objectives

Methods

Results

Conclusion