Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

doi:10.1038/ng.2694

Meta-Analysis

. 2013 Aug;45(8):902-906.

doi: 10.1038/ng.2694. Epub 2013 Jun 30.

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Klaus Bønnelykke^#¹, Melanie C Matheson^#², Tune H Pers^#^{3

4

5

6}, Raquel Granell⁷, David P Strachan⁸, Alexessander Couto Alves⁹, Allan Linneberg¹⁰, John A Curtin¹¹, Nicole M Warrington¹², Marie Standl¹³, Marjan Kerkhof¹⁴, Ingileif Jonsdottir^{15

16}, Blazenka K Bukvic¹⁷, Marika Kaakinen^{18

19}, Patrick Sleimann^{20

21}, Gudmar Thorleifsson¹⁵, Unnur Thorsteinsdottir^{15

16}, Katharina Schramm²², Svetlana Baltic^{23

24}, Eskil Kreiner-Møller¹, Angela Simpson¹¹, Beate St Pourcain⁷, Lachlan Coin⁹, Jennie Hui^{25

26

27

28}, Eugene H Walters²⁹, Carla M T Tiesler¹³, David L Duffy³⁰, Graham Jones³¹; AAGC; Susan M Ring⁷, Wendy L McArdle^{7

8}, Loren Price^{23

24}, Colin F Robertson³², Juha Pekkanen^{33

34}, Clara S Tang³⁰, Elisabeth Thiering¹³, Grant W Montgomery³⁰, Anna-Liisa Hartikainen³⁵, Shyamali C Dharmage², Lise L Husemoen¹⁰, Christian Herder³⁶, John P Kemp⁷, Paul Elliot⁹, Alan James^{28

37

38}, Melanie Waldenberger³⁹, Michael J Abramson⁴⁰, Benjamin P Fairfax⁴¹, Julian C Knight⁴¹, Ramneek Gupta³, Philip J Thompson^{23

24}, Patrick Holt^{42

43}, Peter Sly⁴⁴, Joel N Hirschhorn^{6

45

4

46}, Mario Blekic¹⁷, Stephan Weidinger⁴⁷, Hakon Hakonarsson^{20

21}, Kari Stefansson^{15

16}, Joachim Heinrich¹³, Dirkje S Postma⁴⁸, Adnan Custovic¹¹, Craig E Pennell¹², Marjo-Riitta Jarvelin^{18

19

49

50

51}, Gerard H Koppelman⁵², Nicholas Timpson⁷, Manuel A Ferreira³⁰, Hans Bisgaard¹, A John Henderson⁷

Collaborators, Affiliations

Collaborators

AAGC:
A John Henderson

Affiliations

¹ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood; Health Sciences, University of Copenhagen & Copenhagen University Hospital, Gentofte, Denmark.
² Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
³ Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
⁴ Division of Endocrinology, Children's Hospital, Boston, USA.
⁵ Center for Basic and Translational Obesity Research, Children's Hospital, Boston, USA.
⁶ Broad Institute, Cambridge, USA.
⁷ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁸ Division of Population Health Sciences & Education, St George's, University of London, London, UK.
⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
¹⁰ Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark.
¹¹ University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
¹² School of Women's and Infants' Health, The University of Western Australia, Crawley, Australia.
¹³ Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴ Department of Epidemiology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁵ deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
¹⁶ University of Iceland, 101 Reykjavik, Iceland.
¹⁷ General Hospital "Dr Josip Bencevic" Slavonski Brod, University of Osijek, Osijek, Croatia.
¹⁸ Institute of Health Sciences, University of Oulu, Oulu, Finland.
¹⁹ Biocenter Oulu, University of Oulu, Oulu, Finland.
²⁰ Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
²¹ Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
²² Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²³ Lung Institute of WA, University of WA, Perth, Western Australia, Australia.
²⁴ Centre for Asthma, Allergy and Respiratory Research, University of WA, Perth, Western Australia, Australia.
²⁵ PathWest Laboratory Medicine of Western Australia (WA), Nedlands, Australia.
²⁶ School of Population Health, The University of WA, Nedlands, Australia.
²⁷ School of Pathology and Laboratory Medicine, The University of WA, Nedlands, Australia.
²⁸ Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
²⁹ School of Medicine, University of Tasmania, Hobart, Australia.
³⁰ Queensland Institute of Medical Research, Brisbane, Australia.
³¹ School of Science and Health, University of Western Sydney, Penrith, Australia.
³² Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Australia.
³³ Department of Environmental Health, National Institute for Health and Welfare (THL), Kuopio, Finland.
³⁴ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
³⁵ Department of Clinical Sciences, Obstetrics and Gynecology, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
³⁶ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
³⁷ School of Medicine and Pharmacology, University of WA, Nedlands, Australia.
³⁸ Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia.
³⁹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁴⁰ Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia.
⁴¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴² Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
⁴³ Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
⁴⁴ Queensland Children's Medical Research Institute, University of Queensland, World Health Organization (WHO) Collaborating Centre for Research on Children's Environmental Health, Australia.
⁴⁵ Division of Genetics, Children's Hospital, Boston, USA.
⁴⁶ Department of Genetics, Harvard Medical School, Boston, USA.
⁴⁷ Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴⁸ Department of Pulmonology, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴⁹ Department of Epidemiology and Biostatistics, School of Public Health, MRC-HPA Centre for Environment and Health, Imperial College London, UK.
⁵⁰ National Institute of Health and Welfare, Oulu, Finland.
⁵¹ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁵² Department of Pediatric Pulmonology and Pediatric Allergology , Beatrix Children's Hospital, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

^# Contributed equally.

PMID: 23817571
PMCID: PMC4922420
DOI: 10.1038/ng.2694

Meta-Analysis

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Klaus Bønnelykke et al. Nat Genet. 2013 Aug.

. 2013 Aug;45(8):902-906.

doi: 10.1038/ng.2694. Epub 2013 Jun 30.

Authors

Collaborators

AAGC:
A John Henderson

Affiliations

¹ COPSAC, Copenhagen Prospective Studies on Asthma in Childhood; Health Sciences, University of Copenhagen & Copenhagen University Hospital, Gentofte, Denmark.
² Centre for Molecular, Environmental, Genetic and Analytic Epidemiology, University of Melbourne, Melbourne, Australia.
³ Center for Biological Sequence Analysis, Technical University of Denmark, Lyngby, Denmark.
⁴ Division of Endocrinology, Children's Hospital, Boston, USA.
⁵ Center for Basic and Translational Obesity Research, Children's Hospital, Boston, USA.
⁶ Broad Institute, Cambridge, USA.
⁷ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁸ Division of Population Health Sciences & Education, St George's, University of London, London, UK.
⁹ Department of Epidemiology and Biostatistics, School of Public Health, Imperial College, London, UK.
¹⁰ Research Centre for Prevention and Health, Glostrup Hospital, Glostrup, Denmark.
¹¹ University of Manchester, Manchester Academic Health Science Centre, University Hospital of South Manchester NHS Foundation Trust, Manchester, UK.
¹² School of Women's and Infants' Health, The University of Western Australia, Crawley, Australia.
¹³ Institute of Epidemiology I, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
¹⁴ Department of Epidemiology, Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
¹⁵ deCODE genetics, Sturlugata 8, 101 Reykjavik, Iceland.
¹⁶ University of Iceland, 101 Reykjavik, Iceland.
¹⁷ General Hospital "Dr Josip Bencevic" Slavonski Brod, University of Osijek, Osijek, Croatia.
¹⁸ Institute of Health Sciences, University of Oulu, Oulu, Finland.
¹⁹ Biocenter Oulu, University of Oulu, Oulu, Finland.
²⁰ Center for Applied Genomics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
²¹ Division of Human Genetics, The Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
²² Institute of Human Genetics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
²³ Lung Institute of WA, University of WA, Perth, Western Australia, Australia.
²⁴ Centre for Asthma, Allergy and Respiratory Research, University of WA, Perth, Western Australia, Australia.
²⁵ PathWest Laboratory Medicine of Western Australia (WA), Nedlands, Australia.
²⁶ School of Population Health, The University of WA, Nedlands, Australia.
²⁷ School of Pathology and Laboratory Medicine, The University of WA, Nedlands, Australia.
²⁸ Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Western Australia, Australia.
²⁹ School of Medicine, University of Tasmania, Hobart, Australia.
³⁰ Queensland Institute of Medical Research, Brisbane, Australia.
³¹ School of Science and Health, University of Western Sydney, Penrith, Australia.
³² Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Australia.
³³ Department of Environmental Health, National Institute for Health and Welfare (THL), Kuopio, Finland.
³⁴ Institute of Public Health and Clinical Nutrition, University of Eastern Finland, Kuopio, Finland.
³⁵ Department of Clinical Sciences, Obstetrics and Gynecology, Institute of Clinical Medicine, University of Oulu, Oulu, Finland.
³⁶ Institute for Clinical Diabetology, German Diabetes Center, Leibniz Center for Diabetes Research at Heinrich Heine University Düsseldorf, Düsseldorf, Germany.
³⁷ School of Medicine and Pharmacology, University of WA, Nedlands, Australia.
³⁸ Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia.
³⁹ Research Unit of Molecular Epidemiology, Helmholtz Zentrum München - German Research Center for Environmental Health, Neuherberg, Germany.
⁴⁰ Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia.
⁴¹ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁴² Telethon Institute for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
⁴³ Centre for Child Health Research, The University of Western Australia, Perth, Western Australia, Australia.
⁴⁴ Queensland Children's Medical Research Institute, University of Queensland, World Health Organization (WHO) Collaborating Centre for Research on Children's Environmental Health, Australia.
⁴⁵ Division of Genetics, Children's Hospital, Boston, USA.
⁴⁶ Department of Genetics, Harvard Medical School, Boston, USA.
⁴⁷ Department of Dermatology, Allergology, and Venerology, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany.
⁴⁸ Department of Pulmonology, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.
⁴⁹ Department of Epidemiology and Biostatistics, School of Public Health, MRC-HPA Centre for Environment and Health, Imperial College London, UK.
⁵⁰ National Institute of Health and Welfare, Oulu, Finland.
⁵¹ Unit of Primary Care, Oulu University Hospital, Oulu, Finland.
⁵² Department of Pediatric Pulmonology and Pediatric Allergology , Beatrix Children's Hospital, GRIAC, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

^# Contributed equally.

PMID: 23817571
PMCID: PMC4922420
DOI: 10.1038/ng.2694

Abstract

Allergen-specific immunoglobulin E (present in allergic sensitization) has a central role in the pathogenesis of allergic disease. We performed the first large-scale genome-wide association study (GWAS) of allergic sensitization in 5,789 affected individuals and 10,056 controls and followed up the top SNP at each of 26 loci in 6,114 affected individuals and 9,920 controls. We increased the number of susceptibility loci with genome-wide significant association with allergic sensitization from three to ten, including SNPs in or near TLR6, C11orf30, STAT6, SLC25A46, HLA-DQB1, IL1RL1, LPP, MYC, IL2 and HLA-B. All the top SNPs were associated with allergic symptoms in an independent study. Risk-associated variants at these ten loci were estimated to account for at least 25% of allergic sensitization and allergic rhinitis. Understanding the molecular mechanisms underlying these associations may provide new insights into the etiology of allergic disease.

PubMed Disclaimer

Conflict of interest statement

Competing financial interests

I.J., G.T., U.T. and K. Stefansson are employees of deCODE genetics. The remaining authors declared no competing interests of relevance to this paper.

Figures

**Figure 1. Manhattan plot for the discovery genome-wide association meta-analysis.**

**Figure 2. Gene set enrichment map for the 11 significant gene sets from the MAGENTA analysis.**
Vertices depict pathways and edges depict the mutually overlapping genes, suggesting that significant pathways are highly overlapping.

Figure 3. Combined impact of risk alleles from the 10 genome-wide significant loci on prevalence of allergic sensitization and allergic rhinitis (hay fever) in the population-based Health2006 replication study.
(**a-c**) For each individual a genetic risk score was calculated by applying the per-allele risk estimates from the replication sets, to the number of higher-risk alleles of each of the 10 genome-wide significant loci (one SNP per locus). The risk-score thus represents an index of the number of weighted risk alleles. Along the × axis, individuals in each risk score interval are shown, and the prevalence of sensitization/hay fever in each interval is plotted (y axis on right). The histogram (y axis on left) represents the number of individuals in each risk score interval. (a) Sensitization measured by Skin Prick Test. (b) Sensitization measured by Specific IgE in blood (circles and triangles depict sensitization prevalence with an IgE level cut off of 0.35 IU/mL and 3.5 IU/mL respectively). (c) Hayfever.

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References

1. Johansson SG, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 12. J Allergy Clin Immunol. 2004;113:832–836. - PubMed
1. Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease 10. Lancet. 2008;372:1107–1119. - PubMed
1. Los H, Postmus PE, Boomsma DI. Asthma genetics and intermediate phenotypes: a review from twin studies 1. Twin Res. 2001;4:81–93. - PubMed
1. Thomsen SF, Ulrik CS, Kyvik KO, Ferreira MA, Backer V. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins. Clin Exp Allergy. 2006;36:1382–1390. - PubMed
1. Thomsen SF, van der SS, Kyvik KO, Backer V. A study of asthma severity in adult twins. Clin Respir J. 2012;6:228–237. - PubMed

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[1] Johansson SG, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 12. J Allergy Clin Immunol. 2004;113:832–836. - PubMed

[2] Johansson SG, et al. Revised nomenclature for allergy for global use: Report of the Nomenclature Review Committee of the World Allergy Organization, October 2003 12. J Allergy Clin Immunol. 2004;113:832–836. - PubMed

[3] Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease 10. Lancet. 2008;372:1107–1119. - PubMed

[4] Anderson GP. Endotyping asthma: new insights into key pathogenic mechanisms in a complex, heterogeneous disease 10. Lancet. 2008;372:1107–1119. - PubMed

[5] Los H, Postmus PE, Boomsma DI. Asthma genetics and intermediate phenotypes: a review from twin studies 1. Twin Res. 2001;4:81–93. - PubMed

[6] Los H, Postmus PE, Boomsma DI. Asthma genetics and intermediate phenotypes: a review from twin studies 1. Twin Res. 2001;4:81–93. - PubMed

[7] Thomsen SF, Ulrik CS, Kyvik KO, Ferreira MA, Backer V. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins. Clin Exp Allergy. 2006;36:1382–1390. - PubMed

[8] Thomsen SF, Ulrik CS, Kyvik KO, Ferreira MA, Backer V. Multivariate genetic analysis of atopy phenotypes in a selected sample of twins. Clin Exp Allergy. 2006;36:1382–1390. - PubMed

[9] Thomsen SF, van der SS, Kyvik KO, Backer V. A study of asthma severity in adult twins. Clin Respir J. 2012;6:228–237. - PubMed

[10] Thomsen SF, van der SS, Kyvik KO, Backer V. A study of asthma severity in adult twins. Clin Respir J. 2012;6:228–237. - PubMed

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Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Collaborators

Affiliations

Meta-analysis of genome-wide association studies identifies ten loci influencing allergic sensitization

Authors

Collaborators

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Abstract

Conflict of interest statement

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