A novel role for ciliary function in atopy: ADGRV1 and DNAH5 interactions - 04/05/18
, Emmanuelle Bouzigon, MD, PhD a, ‡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.
Le texte complet de cet article est disponible en PDF.Key words : Atopy, asthma, genetics, genome-wide association study, gene-gene interaction, text mining, ADGRV1, DNAH5, ciliary function
Abbreviations used : ADGRV1, DNAH5, EGEA, GRAIL, GWAS, LD, MRC, MRCA, MRCE, OR, QC, SLSJ, SNP, SPT
Plan
| Supported by the French National Agency for Research (ANR-11-BSV1-027-GWIS-AM; ANR-USPC-2013-EDAGWAS), Université Pierre et Marie Curie doctoral fellowship, and the Canada Research Chair (held by C.L.), and support from the Canadian Institutes of Health Research (CIHR) enabled the maintenance and continuation of the SLSJ asthma study. C.L. is the director of the Asthma Strategic Group of the Respiratory Health Network of the Fonds de la recherche en santé du Québec (FRSQ) and a member of Allergen Network. Genotyping was supported by a grant from the European Commission (no. LSHB-CT-2006-018996-GABRIEL). |
|
| Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest. |
Vol 141 - N° 5
P. 1659 - mai 2018 Retour au numéro
Article précédent
- The activation and function of IL-36? in neutrophilic inflammation in chronic rhinosinusitis
- Hai Wang, Zhi-Yong Li, Wen-Xiu Jiang, Bo Liao, Guan-Ting Zhai, Nan Wang, Zhen Zhen, Jian-wen Ruan, Xiao-Bo Long, Heng Wang, Wei-Hong Liu, Geng-Tian Liang, Wei-Min Xu, Atsushi Kato, Zheng Liu
- Epidermal lipid composition, barrier integrity, and eczematous inflammation are associated with skin microbiome configuration
- Hansjörg Baurecht, Malte C. Rühlemann, Elke Rodríguez, Frederieke Thielking, Inken Harder, Anna-Sophie Erkens, Dora Stölzl, Eva Ellinghaus, Melanie Hotze, Wolfgang Lieb, Sheng Wang, Femke-Anouska Heinsen-Groth, Andre Franke, Stephan Weidinger
Bienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?