A pathway-based association study reveals variants from Wnt signalling genes contributing to asthma susceptibility

Background Genetic susceptibility to asthma is currently linked to a handful of genes which have a limited ability to predict the overall disease risk, suggesting the existence of many other genes involved in disease development. Accumulated evidence from association studies in genes related by biological pathways could reveal novel asthma genes. Objective To reveal novel asthma susceptibility genes by means of a pathway-based association study. Methods Based on summary data from a previous a genomewide association study (GWAS) of asthma, we first identified significant biological pathways using a gene-set enrichment analysis. We then mapped all tested single nucleotide polymorphisms (SNPs) on the genes contributing to significant pathways and prioritized those with a disproportionate number of nominal significant associations for further studies. For those prioritized genes, association studies were performed for selected SNPs in independent case-control samples (n=1765) using logistic regression models, and results were meta-analysed with those from the GWAS. Results Two biological processes were significantly enriched: the cytokine-cytokine receptor interaction (P=0.002) and the Wnt signalling (P=0.012). From the 417 genes interacting in these two pathways, 10 showed an excess of nominal associations, including a known asthma susceptibility locus (encoding SMAD family member 3) and other novel candidate genes. From the latter, association studies of 14 selected SNPs evidenced replication in a locus near the frizzled class receptor 6 (FZD6) gene (P=9.90x10(-4)), which had a consistent direction of effects with the GWAS findings (meta-analysed odds ratio=1.49; P=5.87x10(-6)) and was in high linkage disequilibrium with expression quantitative trait loci in lung tissues. Conclusions and Clinical Relevance This study revealed the importance of two biological pathways in asthma pathogenesis and identified a novel susceptibility locus near Wnt signalling genes.