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

J Allergy Clin Immunol. 2018 May;141(5):1659-1667.e11. doi: 10.1016/j.jaci.2017.06.050. Epub 2017 Sep 18.

Abstract

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 (Pmeta-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.

Keywords: ADGRV1; Atopy; DNAH5; asthma; ciliary function; gene-gene interaction; genetics; genome-wide association study; text mining.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Asthma / genetics
  • Axonemal Dyneins / genetics*
  • Case-Control Studies
  • Epidemiologic Studies
  • Female
  • Genetic Predisposition to Disease / genetics
  • Genome-Wide Association Study / methods
  • Humans
  • Male
  • Polymorphism, Single Nucleotide / genetics*
  • Receptors, G-Protein-Coupled / genetics*

Substances

  • Receptors, G-Protein-Coupled
  • Axonemal Dyneins
  • DNAH5 protein, human