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

Publication date: Available online 18 September 2017
Source:Journal of Allergy and Clinical Immunology
Author(s): Pierre-Emmanuel Sugier, Myriam Brossard, Chloé Sarnowski, Amaury Vaysse, Andréanne Morin, Lucile Pain, Patricia Margaritte-Jeannin, Marie-Hélène Dizier, William O.C.M. Cookson, Mark Lathrop, Miriam F. Moffatt, Catherine Laprise, Florence Demenais, Emmanuelle Bouzigon
BackgroundAtopy, an endotype underlying allergic diseases, has a substantial genetic component.ObjectiveOur goal was to identify novel genes associated with atopy in asthma-ascertained families.MethodsWe implemented a three-step analysis strategy in three datasets: The Epidemiological study on the Genetics and Environment of Asthma (EGEA) dataset: 1,660 subjects; The Saguenay-Lac-Saint-Jean (SLSJ) dataset: 1,138 subjects; and The Medical Research Council (MRC) dataset: 446 subjects). This strategy included a single-SNP genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results and text-mining filtering using GRAIL and SNP-SNP interaction analysis of selected gene pairs.ResultsWe identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, that showed genome-wide significant association with atopy (rs4916831; Pmeta=6.8x10^-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and three genes showing suggestive association with atopy (P≤10^-4). SNP-SNP interaction analysis between ADGRV1 and these three genes showed significant interaction between ADGRV1 rs17554723 and two correlated SNPs (rs2134256 and rs1354187) within dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int=3.6x10^-5 and 6.1x10^-5, that met the multiple-testing corrected threshold of 7.3x10^-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723.ConclusionAs both DNAH5 and ADGRV1 contribute to function of cilia, this study suggests that cilia dysfunction may 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.

Teaser

This study in three family-based studies identified association between ADGRV1 and atopy and interaction between ADGRV1 and DNAH5, two genes that contribute to ciliary functions.


http://ift.tt/2xj3vtd