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

William Murk, Andrew T. DeWan

Many 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. A 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 × 10(10) 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. Using 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.