Asthma-susceptibility variants identified using probands in case-control and family-based analyses

Blanca E Himes,Benjamin A Raby,Jemma B Wilk,Gary M Hunninghake,Edwin K Silverman,Barbara Klanderman,Ann C Wu,Scott T Weiss,Christoph Lange,Lydiana Avila,Jessica Lasky-Su,George T O'Connor,Amy J Murphy,Manuel E Soto-Quiros,Juan C Celedón,Ross Lazarus

doi:10.1186/1471-2350-11-122

Abstract

BackgroundAsthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs.MethodsWe used probands from the Childhood Asthma Management Program (CAMP) in two primary genome-wide association study designs: (1) probands were combined with publicly available population controls in a case-control design, and (2) probands and their parents were used in a family-based design. We followed a two-stage replication process utilizing three independent populations to validate our primary findings.ResultsWe found that single nucleotide polymorphisms with similar case-control and family-based association results were more likely to replicate in the independent populations, than those with the smallest p-values in either the case-control or family-based design alone. The single nucleotide polymorphism that showed the strongest evidence for association to asthma was rs17572584, which replicated in 2/3 independent populations with an overall p-value among replication populations of 3.5E-05. This variant is near a gene that encodes an enzyme that has been implicated to act coordinately with modulators of Th2 cell differentiation and is expressed in human lung.ConclusionsOur results suggest that using probands from family-based studies in case-control designs, and combining results of both family-based and case-control approaches, may be a way to augment our ability to find SNPs associated with asthma and other complex diseases.

Highlights

Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies
In the family-based genome-wide association (GWA) (i.e. Childhood Asthma Management Program (CAMP) Trio study), 534,290 SNPs in 403 trios were ranked according to PBAT additive model p-values, and 13 SNPs had p-values less than a nominally significant level of 1E-05
We found that 10 SNPs had a p-value < 0.05 in Framingham Heart Study (FHS) or i2b2 Crimson Asthma Project (iCAP) and had the same direction of BP CAMP/ CAMP CAMP/ CAMP Illumina Trio Illumina Trio

Summary

Introduction

Asthma is a chronic respiratory disease whose genetic basis has been explored for over two decades, most recently via genome-wide association studies. We sought to find asthma-susceptibility variants by using probands from a single population in both family-based and case-control association designs. Asthma [MIM 600807] is a chronic respiratory disease that affects over 20 million Americans and 300 million people worldwide [1,2]. Genome-wide association (GWA) studies of asthma have found that variants in or near several genes, including ORMDL3 [MIM 610075]. The primary findings of the PDE4D GWA study were obtained in a case-control design consisting of children from an asthma clinical trial and publicly available population controls. We used a case-control design, genetic studies of these asthmatic children were originally intended to be part of a family-based design, as DNA was collected from children and their parents. We chose the case-control design in an effort to increase the power to detect genetic associations

Methods

Results

Conclusion