Genome-wide search identifies a gene-gene interaction between 20p13 and 2q14 in asthma

William Murk,Andrew T Dewan

doi:10.1186/s12863-016-0376-3

Abstract

BackgroundMany studies have attempted to identify gene-gene interactions affecting asthma susceptibility. However, these studies have typically used candidate gene approaches in limiting the genetic search space, and there have been few searches for gene-gene interactions on a genome-wide scale. We aimed to conduct a genome-wide gene-gene interaction study for asthma, using data from the GABRIEL Consortium.ResultsA two-stage study design was used, including a screening analysis (N = 1625 subjects) and a follow-up analysis (N = 5264 subjects). In the screening analysis, all pairwise interactions among 301,547 SNPs were evaluated, encompassing a total of 4.55 × 1010 interactions. Those with a screening interaction p-value < 10−5 were evaluated in the follow-up analysis. No interaction selected from the screening analysis met strict statistical significance in the follow-up (p-value < 1.45 × 10−7). However, the top-ranked interaction (rs910652 [20p13] × rs11684871 [2q14]) in the follow-up (p-value = 1.58 × 10−6) was significant in one component of a replication analysis. This interaction was notable in that rs910652 is located within 78 kilobases of ADAM33, which is one of the most well studied asthma susceptibility genes. In addition, rs11684871 is located in or near GLI2, which may have biologically relevant roles in asthma.ConclusionsUsing a genome-wide approach, we identified and found suggestive evidence of replication for a gene-gene interaction in asthma involving loci that are potentially highly relevant in asthma pathogenesis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-016-0376-3) contains supplementary material, which is available to authorized users.

Highlights

Many studies have attempted to identify gene-gene interactions affecting asthma susceptibility
An alternative explanation is that HSPA12B itself is the functional gene of the interaction on chromosome 20. This gene does not have a clear role in asthma, but one study has reported its association with lung function at the same single nucleotide polymorphism (SNP) we identified [19]
In summary, using a genome-wide approach of screening for gene-gene interactions, we identified and found suggestive evidence of replication for an interaction in asthma, where one of the participating SNPs is in close proximity to ADAM33 and the other is located in or near GLI2

Summary

Introduction

Many studies have attempted to identify gene-gene interactions affecting asthma susceptibility These studies have typically used candidate gene approaches in limiting the genetic search space, and there have been few searches for gene-gene interactions on a genome-wide scale. More than 45 studies have attempted to identify gene-gene interactions in asthma, with over 190 significant interactions reported far [10] These studies have tended to use candidate gene approaches to narrow the genetic space in which to search for interactions, typically focusing on loci that have been reported to show significant marginal effects (i.e., effects that manifest when loci are assessed individually). Only one asthma association study involving a genome-wide search for gene-gene interactions has been published, with null findings [11]. This may be due in part to the lower likelihood of publication of null findings, it appears that the search space of pairwise interactions has been sparsely explored in asthma

Objectives

Methods

Results

Discussion

Conclusion