Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

Manuel A R Ferreira, Rick Jansen, Gonneke Willemsen, Brenda W. 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 & 3 others Rhiannon B. Werder, Simon Phipps, Australian Asthma Genetics Consortium Collaborators

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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.

Original languageEnglish
Pages (from-to)1148-1157
Number of pages10
JournalJournal of Allergy and Clinical Immunology
Volume139
Issue number4
DOIs
Publication statusPublished - 1 Apr 2017

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Quantitative Trait Loci
Asthma
Nucleotides
Genome-Wide Association Study
Genes
Eosinophils
Uridine Diphosphate Sugars
Allergens
Adenosine Diphosphate
Neutrophils
Software
Epithelial Cells
Gene Expression
Lung

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Ferreira, M. A. R., Jansen, R., Willemsen, G., Penninx, B. W., Bain, L. M., Vicente, C. T., ... Australian Asthma Genetics Consortium Collaborators (2017). Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling. Journal of Allergy and Clinical Immunology, 139(4), 1148-1157. https://doi.org/10.1016/j.jaci.2016.07.017
Ferreira, Manuel A R ; Jansen, Rick ; Willemsen, Gonneke ; Penninx, Brenda W. ; Bain, Lisa M. ; Vicente, Cristina T. ; Revez, Joana A. ; Matheson, Melanie C. ; Hui, Jennie ; Tung, Joyce Y. ; Baltic, Svetlana ; Le Souëf, Peter ; Montgomery, Grant W. ; Martin, Nicholas G. ; Robertson, Colin F. ; James, Alan ; Thompson, Philip J. ; Boomsma, Dorret I. ; Hopper, John L. ; Hinds, David A. ; Werder, Rhiannon B. ; Phipps, Simon ; Australian Asthma Genetics Consortium Collaborators. / Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling. In: Journal of Allergy and Clinical Immunology. 2017 ; Vol. 139, No. 4. pp. 1148-1157.
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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.",
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author = "Ferreira, {Manuel A R} and Rick Jansen and Gonneke Willemsen and Penninx, {Brenda W.} and Bain, {Lisa M.} and Vicente, {Cristina T.} and Revez, {Joana A.} and Matheson, {Melanie C.} and Jennie Hui and Tung, {Joyce Y.} and Svetlana Baltic and {Le Sou{\"e}f}, Peter and Montgomery, {Grant W.} and Martin, {Nicholas G.} and Robertson, {Colin F.} and Alan James and Thompson, {Philip J.} and Boomsma, {Dorret I.} and Hopper, {John L.} and Hinds, {David A.} and Werder, {Rhiannon B.} and Simon Phipps and {Australian Asthma Genetics Consortium Collaborators}",
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Ferreira, MAR, Jansen, R, Willemsen, G, Penninx, BW, Bain, LM, Vicente, CT, Revez, JA, Matheson, MC, Hui, J, Tung, JY, Baltic, S, Le Souëf, P, Montgomery, GW, Martin, NG, Robertson, CF, James, A, Thompson, PJ, Boomsma, DI, Hopper, JL, Hinds, DA, Werder, RB, Phipps, S & Australian Asthma Genetics Consortium Collaborators 2017, 'Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling' Journal of Allergy and Clinical Immunology, vol. 139, no. 4, pp. 1148-1157. https://doi.org/10.1016/j.jaci.2016.07.017

Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling. / Ferreira, Manuel A R; Jansen, Rick; Willemsen, Gonneke; Penninx, Brenda W.; Bain, Lisa M.; Vicente, Cristina T.; Revez, Joana A.; Matheson, Melanie C.; Hui, Jennie; Tung, Joyce Y.; Baltic, Svetlana; Le Souëf, Peter; Montgomery, Grant W.; Martin, Nicholas G.; Robertson, Colin F.; James, Alan; Thompson, Philip J.; Boomsma, Dorret I.; Hopper, John L.; Hinds, David A.; Werder, Rhiannon B.; Phipps, Simon; Australian Asthma Genetics Consortium Collaborators.

In: Journal of Allergy and Clinical Immunology, Vol. 139, No. 4, 01.04.2017, p. 1148-1157.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling

AU - Ferreira, Manuel A R

AU - Jansen, Rick

AU - Willemsen, Gonneke

AU - Penninx, Brenda W.

AU - Bain, Lisa M.

AU - Vicente, Cristina T.

AU - Revez, Joana A.

AU - Matheson, Melanie C.

AU - Hui, Jennie

AU - Tung, Joyce Y.

AU - Baltic, Svetlana

AU - Le Souëf, Peter

AU - Montgomery, Grant W.

AU - Martin, Nicholas G.

AU - Robertson, Colin F.

AU - James, Alan

AU - Thompson, Philip J.

AU - Boomsma, Dorret I.

AU - Hopper, John L.

AU - Hinds, David A.

AU - Werder, Rhiannon B.

AU - Phipps, Simon

AU - Australian Asthma Genetics Consortium Collaborators

PY - 2017/4/1

Y1 - 2017/4/1

N2 - 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.

AB - 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.

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KW - CLK3

KW - EUGENE

KW - expression quantitative trait locus

KW - Inflammation

KW - obesity

KW - P2Y13

KW - P2Y14

KW - predisposition

KW - PrediXcan

KW - transcriptome

KW - TWAS

KW - UDP-glucose

KW - VEGAS

KW - ZNF707

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DO - 10.1016/j.jaci.2016.07.017

M3 - Article

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SP - 1148

EP - 1157

JO - The Journal of Allergy and Clinical Immunology

JF - The Journal of Allergy and Clinical Immunology

SN - 0091-6749

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