Eleven loci with new reproducible genetic associations with allergic disease risk

23Andme Research Team

Research output: Contribution to JournalArticleAcademicpeer-review

Abstract

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.

Original languageEnglish
Pages (from-to)691-699
Number of pages9
JournalJournal of Allergy and Clinical Immunology
Volume143
Issue number2
DOIs
Publication statusPublished - Feb 2019

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Genome-Wide Association Study
Genes
Interleukin-27
Seasonal Allergic Rhinitis
Eczema
Hypersensitivity
Asthma
Gene Expression
Genetic Loci
Cytokines
Therapeutics
Pharmaceutical Preparations

Cite this

@article{3f7b01b2fba445c4b340e79397a56261,
title = "Eleven loci with new reproducible genetic associations with allergic disease risk",
abstract = "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.",
author = "Ferreira, {Manuel A.R.} and Vonk, {Judith M} and Hansj{\"o}rg Baurecht and Ingo Marenholz and Chao Tian and Hoffman, {Joshua D} and Quinta Helmer and Annika Tillander and Vilhelmina Ullemar and Yi Lu and Franz R{\"u}schendorf and Hinds, {David A} and Norbert H{\"u}bner and Stephan Weidinger and Magnusson, {Patrik Ke} and Eric Jorgenson and Young-Ae Lee and Boomsma, {Dorret I} and Robert Karlsson and Catarina Almqvist and Koppelman, {Gerard H} and Lavinia Paternoster and {23Andme Research Team}",
note = "Copyright {\circledC} 2018. Published by Elsevier Inc.",
year = "2019",
month = "2",
doi = "10.1016/j.jaci.2018.03.012",
language = "English",
volume = "143",
pages = "691--699",
journal = "Journal of Allergy and Clinical Immunology",
issn = "0091-6749",
publisher = "Mosby Inc.",
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}

Eleven loci with new reproducible genetic associations with allergic disease risk. / 23Andme Research Team.

In: Journal of Allergy and Clinical Immunology, Vol. 143, No. 2, 02.2019, p. 691-699.

Research output: Contribution to JournalArticleAcademicpeer-review

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

Y1 - 2019/2

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.

U2 - 10.1016/j.jaci.2018.03.012

DO - 10.1016/j.jaci.2018.03.012

M3 - Article

VL - 143

SP - 691

EP - 699

JO - Journal of Allergy and Clinical Immunology

JF - Journal of Allergy and Clinical Immunology

SN - 0091-6749

IS - 2

ER -