Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling - 19/04/17
, Rick Jansen, PhD b, Gonneke Willemsen, PhD c, Brenda Penninx, PhD b, Lisa M. Bain, BSc a, Cristina T. Vicente, BSc a, Joana A. Revez, BSc a, Melanie C. Matheson, PhD d, Jennie Hui, PhD e, f, g, h, Joyce Y. Tung, PhD i, Svetlana Baltic, PhD j, Peter Le Souëf, FRACP k, Grant W. Montgomery, PhD a, Nicholas G. Martin, PhD a, Colin F. Robertson, FRACP l, Alan James, FRACP h, m, n, Philip J. Thompson, FRACP j, m, Dorret I. Boomsma, PhD c, John L. Hopper, PhD d, David A. Hinds, PhD i, Rhiannon B. Werder, B Biomed Sc o, ∗, Simon Phipps, PhD o, ∗and the
Australian Asthma Genetics Consortium Collaborators‡
Abstract |
Background |
Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed.
Objective |
We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes.
Methods |
We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations.
Results |
We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14—purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively—were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.
Conclusion |
We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.
Le texte complet de cet article est disponible en PDF.Key words : Inflammation, expression quantitative trait locus, transcriptome, predisposition, obesity, EUGENE, VEGAS, PrediXcan, TWAS, ZNF707, AOAH, CLK3, UDP-glucose, P2Y14, P2Y13
Abbreviations used : ADP, AEC, ATP, BALF, eQTL, FDR, GWAS, HDM, LD, SNP, UDP
Plan
| Supported in part by the National Human Genome Research Institute of the National Institutes of Health (R44HG006981) and the National Health and Medical Research Council of Australia (613627 and APP1036550). |
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| Disclosure of potential conflict of interest: M. A. R. Ferreira receives grant support from the National Health and Medical Research Council of Australia (grants 613627 and APP1036550). S. Phipps receives grant support from Pfizer. The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 139 - N° 4
P. 1148-1157 - avril 2017 Retour au numéro
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