Gene-based analysis of regulatory variants identifies four putative novel asthma risk genes related to nucleotide synthesis and signaling

Publication date: Available online 20 August 2016
Source:Journal of Allergy and Clinical Immunology
Author(s): Manuel A.R. Ferreira, Rick Jansen, Gonneke Willemsen, Brenda Penninx, Lisa M. Bain, Cristina T. Vicente, Joana A. Revez, Melanie C. Matheson, Jennie Hui, Joyce Y. Tung, Svetlana Baltic, Peter Le Souëf, Grant W. Montgomery, Nicholas G. Martin, Colin F. Robertson, Alan James, Philip J. Thompson, Dorret I. Boomsma, John L. Hopper, David A. Hinds, Rhiannon B. Werder, Simon Phipps
BackgroundHundreds 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 (GWAS) to identify risk-associated variants are needed.ObjectiveTo 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.MethodsWe 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 two published asthma GWAS (combined N=46,044) and used mouse studies to provide initial functional insights into two genes with novel genetic associations.ResultsWe tested the association between asthma and 17,190 genes which were found to have cis-and/or trans-eQTLs across 16 published eQTL studies. At an empirical false discovery rate 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 six genes not previously implicated in disease aetiology (eg. LIMS1, TINF2 and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with four 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 ADP and UDP-sugars, respectively – were up-regulated after allergen challenge, notably in airway epithelial cells, eosinophils and neutrophils. Intranasal exposure with the receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.ConclusionWe identified novel associations between asthma and eQTLs for four genes related to nucleotide synthesis/signaling, and demonstrate the power of gene-based analyses of GWAS.

Teaser

Using a new method for gene-based analysis of GWAS results, we identified a genetic association between asthma risk and eQTLs for B4GALT3 and USMG5, which are involved in the production of UDP-galactose and ATP respectively, and P2RY13 and P2RY14, two G protein-coupled receptors activated respectively by ADP and UDP-sugars. Functional studies in the mouse show that activation of P2ry13 or P2ry14 induces the release of IL-33 and eosinophil infiltration into the lungs, in the absence of allergen stimulation. Functional studies that characterize in depth the contribution of these four genes to asthma pathophysiology are warranted.


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