Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

doi:10.1016/j.jaci.2013.10.030

. 2014 Jun;133(6):1564-71.

doi: 10.1016/j.jaci.2013.10.030. Epub 2013 Dec 31.

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Manuel A R Ferreira¹, Melanie C Matheson², Clara S Tang³, Raquel Granell⁴, Wei Ang⁵, Jennie Hui⁶, Amy K Kiefer⁷, David L Duffy⁸, Svetlana Baltic⁹, Patrick Danoy¹⁰, Minh Bui², Loren Price⁹, Peter D Sly¹¹, Nicholas Eriksson⁷, Pamela A Madden¹², Michael J Abramson¹³, Patrick G Holt¹⁴, Andrew C Heath¹², Michael Hunter¹⁵, Bill Musk¹⁶, Colin F Robertson¹⁷, Peter Le Souëf¹⁸, Grant W Montgomery⁸, A John Henderson⁴, Joyce Y Tung⁷, Shyamali C Dharmage², Matthew A Brown¹⁰, Alan James¹⁹, Philip J Thompson⁹, Craig Pennell⁵, Nicholas G Martin⁸, David M Evans²⁰, David A Hinds⁷, John L Hopper²¹; Australian Asthma Genetics Consortium Collaborators

Collaborators, Affiliations

Collaborators

Australian Asthma Genetics Consortium Collaborators:
Dale R Nyholta, John Beilbyb-d, Faang Cheahe, Desiree Mészárosf, Scott D Gordona, Melissa C Southeyg, Margaret J Wrighta, James Markosh, Li P Chunge, Anjali K Hendersa, Graham Gilesi, Suzanna Templee, John Whitfielda, Brad Sheltone, Chalermchai Mitrpante, Mark Jenkinsj, Haydn Waltersf

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
² Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, Australia; Departments of Psychiatry, Surgery, and Medicine, Centre for Genomic Sciences, University of Hong Kong, Hong Kong, China.
⁴ School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
⁵ School of Women's and Infant's Health, University of Western Australia, Subiaco, Australia.
⁶ PathWest Laboratory Medicine of Western Australia, Nedlands, Australia; School of Population Health, University of Western Australia, Nedlands, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.
⁷ 23andMe, Mountain View, Calif.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹ Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, Australia.
¹⁰ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
¹¹ Queensland Children's Medical Research Institute, Royal Children's Hospital, Brisbane, Australia.
¹² Department of Psychiatry, Washington University School, of Medicine, St Louis, Mo.
¹³ Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia.
¹⁴ Telethon Institute of Child Health Research, University of Western Australia, Subiaco, Australia.
¹⁵ School of Population Health, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁶ School of Population Health, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁷ Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁸ School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Perth, Australia.
¹⁹ Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia.
²⁰ School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom; Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom.
²¹ Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia. Electronic address: j.hopper@unimelb.edu.au.

PMID: 24388013
PMCID: PMC4280183
DOI: 10.1016/j.jaci.2013.10.030

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Manuel A R Ferreira et al. J Allergy Clin Immunol. 2014 Jun.

. 2014 Jun;133(6):1564-71.

doi: 10.1016/j.jaci.2013.10.030. Epub 2013 Dec 31.

Authors

Collaborators

Australian Asthma Genetics Consortium Collaborators:
Dale R Nyholta, John Beilbyb-d, Faang Cheahe, Desiree Mészárosf, Scott D Gordona, Melissa C Southeyg, Margaret J Wrighta, James Markosh, Li P Chunge, Anjali K Hendersa, Graham Gilesi, Suzanna Templee, John Whitfielda, Brad Sheltone, Chalermchai Mitrpante, Mark Jenkinsj, Haydn Waltersf

Affiliations

¹ QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
² Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, Australia; Departments of Psychiatry, Surgery, and Medicine, Centre for Genomic Sciences, University of Hong Kong, Hong Kong, China.
⁴ School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom.
⁵ School of Women's and Infant's Health, University of Western Australia, Subiaco, Australia.
⁶ PathWest Laboratory Medicine of Western Australia, Nedlands, Australia; School of Population Health, University of Western Australia, Nedlands, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.
⁷ 23andMe, Mountain View, Calif.
⁸ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁹ Lung Institute of Western Australia and Centre for Asthma, Allergy and Respiratory Research, University of Western Australia, Perth, Australia.
¹⁰ University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia.
¹¹ Queensland Children's Medical Research Institute, Royal Children's Hospital, Brisbane, Australia.
¹² Department of Psychiatry, Washington University School, of Medicine, St Louis, Mo.
¹³ Department of Epidemiology & Preventive Medicine, Monash University, Melbourne, Australia.
¹⁴ Telethon Institute of Child Health Research, University of Western Australia, Subiaco, Australia.
¹⁵ School of Population Health, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁶ School of Population Health, University of Western Australia, Nedlands, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Department of Respiratory Medicine, Sir Charles Gairdner Hospital, Perth, Australia.
¹⁷ Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Australia.
¹⁸ School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Perth, Australia.
¹⁹ Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Perth, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Department of Pulmonary Physiology, West Australian Sleep Disorders Research Institute, Nedlands, Australia.
²⁰ School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom; Medical Research Council (MRC) Centre for Causal Analyses in Translational Epidemiology, University of Bristol, Bristol, United Kingdom.
²¹ Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia. Electronic address: j.hopper@unimelb.edu.au.

PMID: 24388013
PMCID: PMC4280183
DOI: 10.1016/j.jaci.2013.10.030

Abstract

Background: To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever.

Objective: We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases.

Methods: We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091).

Results: At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10(-9)) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10(-8)). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10(-7)) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10(-6)).

Conclusion: By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency.

Keywords: Rhinitis; atopy; bivariate; genetic correlation; selection; single nucleotide polymorphism.

PubMed Disclaimer

Conflict of interest statement

Disclosure of potential conflict of interest: M. A. R. Ferreira has received research support from the Australian National Health and Medical Research Council (NHMRC). A. K. Kiefer has received research support from the National Institutes of Health (NIH) and is employed by and has stock/stock options in 23andMe. D. L Duffy has received research support from the NHMRC. N. Eriksson has received research support from the NIH and is employed by and has stock/stock options in 23andMe. P. A. Madden has received research support from the NIH (R01DA012854 [NAG] and R25DA027995 [R25]) and has received lecture fees. M. J. Abramson has received research support from Pfizer and has received travel support from Boehringer Ingelheim. A. C. Heath has received research support from the National Institutes of Health. C. F. Robertson has received research support from the NHMRC (grants 436959, 490321, 491246, 1006215, 044816, and 1044829), the MCRI, the US Cystic Fibrosis Foundation, the Australian Cystic Fibrosis Research Trust, and the NHMRC Centre for Research Excellence. G. W. Montgomery has received research support from the NHMRC. A. J. Henderson has received research support from the Medical Research Council UK and the Wellcome Trust. J. Y. Tung has received research support from the NIH (1R43HL115873-01) and is employed by and has stock/stock options in 23andMe. C. Pennell has received research support from the NHMRC (APP572613, 2009–2012), the NIH, CIHR, and Channel 7 Telethon; is a board member for the Raine Executive Committee; is employed by the University of Western Australia; has patents from the United States; and has received travel expenses from the March of Dimes Preventing Prematurity meeting, the GAPPS meeting, and PreHOT meetings from 2009–2012. D. M. Evans has received research support from the MRC and the Wellcome trust (supply core support to Avon Longitudinal Study of Parents and Their Children). D. A. Hinds has received research support from the NIH (1R43HL115873-01) and is employed by and has stock/stock options in 23andMe. The rest of the authors declare that they have no relevant conflicts of interest.

Figures

**FIG. 1**
Effect (OR ±95% CI) of the top 11 loci on the mutually exclusive phenotypes of asthma without hay fever (A+H−) and hay fever without asthma (A−H+). Results are based on the comparison between 14,091 control subjects (no asthma and no hay fever, A−H−) and either 2,776 asthma without hay fever (A+H−) cases or 9,301 hay fever without asthma (A−H+) cases.

See this image and copyright information in PMC

Cited by

A novel mouse model for the identification of thioredoxin-1 protein interactions.
Booze ML, Hansen JM, Vitiello PF. Booze ML, et al. Free Radic Biol Med. 2016 Oct;99:533-543. doi: 10.1016/j.freeradbiomed.2016.09.013. Epub 2016 Sep 14. Free Radic Biol Med. 2016. PMID: 27639450 Free PMC article.
eQTL of bronchial epithelial cells and bronchial alveolar lavage deciphers GWAS-identified asthma genes.
Li X, Hastie AT, Hawkins GA, Moore WC, Ampleford EJ, Milosevic J, Li H, Busse WW, Erzurum SC, Kaminski N, Wenzel SE, Meyers DA, Bleecker ER. Li X, et al. Allergy. 2015 Oct;70(10):1309-18. doi: 10.1111/all.12683. Epub 2015 Jul 24. Allergy. 2015. PMID: 26119467 Free PMC article.
TSLP disease-associated genetic variants combined with airway TSLP expression influence asthma risk.
Murrison LB, Ren X, Preusse K, He H, Kroner J, Chen X, Jenkins S, Johansson E, Biagini JM, Weirauch MT, Kopan R, Martin LJ, Khurana Hershey GK. Murrison LB, et al. J Allergy Clin Immunol. 2022 Jan;149(1):79-88. doi: 10.1016/j.jaci.2021.05.033. Epub 2021 Jun 7. J Allergy Clin Immunol. 2022. PMID: 34111451 Free PMC article.
eQTL discovery and their association with severe equine asthma in European Warmblood horses.
Mason VC, Schaefer RJ, McCue ME, Leeb T, Gerber V. Mason VC, et al. BMC Genomics. 2018 Aug 2;19(1):581. doi: 10.1186/s12864-018-4938-9. BMC Genomics. 2018. PMID: 30071827 Free PMC article.
Identification of a Novel Pyroptosis-Related Gene Signature Indicative of Disease Prognosis and Treatment Response in Skin Cutaneous Melanoma.
Li AA, Zhang Y, Tong WL, Chen JW, Huang SH, Liu JM, Liu ZL. Li AA, et al. Int J Gen Med. 2022 Jul 12;15:6145-6163. doi: 10.2147/IJGM.S367693. eCollection 2022. Int J Gen Med. 2022. PMID: 35855761 Free PMC article.

See all "Cited by" articles

References

1. Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002;109:419–25. - PubMed
1. Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;104:301–4. - PubMed
1. Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–57. - PubMed
1. Burgess JA, Walters EH, Byrnes GB, Matheson MC, Jenkins MA, Wharton CL, et al. Childhood allergic rhinitis predicts asthma incidence and persistence to middle age: a longitudinal study. J Allergy Clin Immunol. 2007;120:863–9. - PubMed
1. Togias A. Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol. 2003;111:1171–84. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Substances

Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Other Literature Sources
- The Lens - Patent Citations Database
- scite Smart Citations
Medical
- MedlinePlus Consumer Health Information
- MedlinePlus Health Information

[1] Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002;109:419–25. - PubMed

[2] Guerra S, Sherrill DL, Martinez FD, Barbee RA. Rhinitis as an independent risk factor for adult-onset asthma. J Allergy Clin Immunol. 2002;109:419–25. - PubMed

[3] Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;104:301–4. - PubMed

[4] Leynaert B, Bousquet J, Neukirch C, Liard R, Neukirch F. Perennial rhinitis: An independent risk factor for asthma in nonatopic subjects: results from the European Community Respiratory Health Survey. J Allergy Clin Immunol. 1999;104:301–4. - PubMed

[5] Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–57. - PubMed

[6] Shaaban R, Zureik M, Soussan D, Neukirch C, Heinrich J, Sunyer J, et al. Rhinitis and onset of asthma: a longitudinal population-based study. Lancet. 2008;372:1049–57. - PubMed

[7] Burgess JA, Walters EH, Byrnes GB, Matheson MC, Jenkins MA, Wharton CL, et al. Childhood allergic rhinitis predicts asthma incidence and persistence to middle age: a longitudinal study. J Allergy Clin Immunol. 2007;120:863–9. - PubMed

[8] Burgess JA, Walters EH, Byrnes GB, Matheson MC, Jenkins MA, Wharton CL, et al. Childhood allergic rhinitis predicts asthma incidence and persistence to middle age: a longitudinal study. J Allergy Clin Immunol. 2007;120:863–9. - PubMed

[9] Togias A. Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol. 2003;111:1171–84. - PubMed

[10] Togias A. Rhinitis and asthma: evidence for respiratory system integration. J Allergy Clin Immunol. 2003;111:1171–84. - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Collaborators

Affiliations

Genome-wide association analysis identifies 11 risk variants associated with the asthma with hay fever phenotype

Authors

Collaborators

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Publication types

MeSH terms

Substances

Related information

Grants and funding

LinkOut - more resources

Full Text Sources

Other Literature Sources

Medical