TY - JOUR
T1 - Eleven loci with new reproducible genetic associations with allergic disease risk
AU - Ferreira, Manuel A.R.
AU - Vonk, Judith M
AU - Baurecht, Hansjörg
AU - Marenholz, Ingo
AU - Tian, Chao
AU - Hoffman, Joshua D
AU - Helmer, Quinta
AU - Tillander, Annika
AU - Ullemar, Vilhelmina
AU - Lu, Yi
AU - Rüschendorf, Franz
AU - Hinds, David A
AU - Hübner, Norbert
AU - Weidinger, Stephan
AU - Magnusson, Patrik Ke
AU - Jorgenson, Eric
AU - Lee, Young-Ae
AU - Boomsma, Dorret I
AU - Karlsson, Robert
AU - Almqvist, Catarina
AU - Koppelman, Gerard H
AU - Paternoster, Lavinia
AU - 23Andme Research Team
N1 - Copyright © 2018. Published by Elsevier Inc.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.OBJECTIVE: To identify novel risk loci shared between asthma, hay fever and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 individuals.METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analysed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 individuals from the UK Biobank study.RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P-value of 2.5x10-6. Of these, 20 were also significantly associated (P<0.05/30=0.0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWAS. Amongst these were nine genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L and LAT. For four genes (e.g. ATXN2L), a genetically-determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress Th2 responses.CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWAS. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
AB - BACKGROUND: A recent genome-wide association study (GWAS) identified 99 loci that contain genetic risk variants shared between asthma, hay fever and eczema. Many more risk loci shared between these common allergic diseases remain to be discovered, which could point to new therapeutic opportunities.OBJECTIVE: To identify novel risk loci shared between asthma, hay fever and eczema by applying a gene-based test of association to results from a published GWAS that included data from 360,838 individuals.METHODS: We used approximate conditional analysis to adjust the results from the published GWAS for the effects of the top risk variants identified in that study. We then analysed the adjusted GWAS results with the EUGENE gene-based approach, which combines evidence for association with disease risk across regulatory variants identified in different tissues. Novel gene-based associations were followed up in an independent sample of 233,898 individuals from the UK Biobank study.RESULTS: Of the 19,432 genes tested, 30 had a significant gene-based association at a Bonferroni-corrected P-value of 2.5x10-6. Of these, 20 were also significantly associated (P<0.05/30=0.0016) with disease risk in the replication sample, including 19 that were located in 11 loci not reported to contain allergy risk variants in previous GWAS. Amongst these were nine genes with a known function that is directly relevant to allergic disease: FOSL2, VPRBP, IPCEF1, PRR5L, NCF4, APOBR, IL27, ATXN2L and LAT. For four genes (e.g. ATXN2L), a genetically-determined decrease in gene expression was associated with decreased allergy risk, and therefore drugs that inhibit gene expression or function are predicted to ameliorate disease symptoms. The opposite directional effect was observed for 14 genes, including IL27, a cytokine known to suppress Th2 responses.CONCLUSION: Using a gene-based approach, we identified 11 risk loci for allergic disease that were not reported in previous GWAS. Functional studies that investigate the contribution of the 19 associated genes to the pathophysiology of allergic disease and assess their therapeutic potential are warranted.
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U2 - 10.1016/j.jaci.2018.03.012
DO - 10.1016/j.jaci.2018.03.012
M3 - Article
C2 - 29679657
SN - 0091-6749
VL - 143
SP - 691
EP - 699
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 2
ER -
