A novel role for ciliary function in atopy: ADGRV1 and DNAH5 interactions.

BACKGROUND:Atopy, an endotype underlying allergic diseases, has a substantial genetic component. OBJECTIVE:Our goal was to identify novel genes associated with atopy in asthma-ascertained families. METHODS:We implemented a 3-step analysis strategy in 3 data sets: the Epidemiological Study on the Genetics and Environment of Asthma (EGEA) data set (1660 subjects), the Saguenay-Lac-Saint-Jean study data set (1138 subjects), and the Medical Research Council (MRC) data set (446 subjects). This strategy included a single nucleotide polymorphism (SNP) genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results, and text-mining filtering using Gene Relationships Across Implicated Loci and SNP-SNP interaction analysis of selected gene pairs. RESULTS:We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, which showed genome-wide significant association with atopy (rs4916831, meta-analysis P value = 6.8 × 10^-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and 3 genes showing suggestive association with atopy (P ≤ 10^-4). SNP-SNP interaction analysis between ADGRV1 and these 3 genes showed significant interaction between ADGRV1 rs17554723 and 2 correlated SNPs (rs2134256 and rs1354187) within the dynein axonemal heavy chain 5 (DNAH5) gene (P_meta-int = 3.6 × 10^-5 and 6.1 × 10^-5, which met the multiple-testing corrected threshold of 7.3 × 10^-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723. CONCLUSION:Because both DNAH5 and ADGRV1 contribute to ciliary function, this study suggests that ciliary dysfunction might represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

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