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

Manuel A R Ferreira; Melanie C Matheson; Clara S Tang; Raquel Granell; Wei Ang; Jennie Hui; Amy K Kiefer; David L Duffy; Svetlana Baltic; Patrick Danoy; Minh Bui; Loren Price; Peter D Sly; Nicholas Eriksson; Pamela A Madden; Michael J Abramson; Patrick G Holt; Andrew C Heath; Michael Hunter; Bill Musk; Colin F Robertson; Peter Le Souëf; Grant W Montgomery; A John Henderson; Joyce Y Tung; Shyamali C Dharmage; Matthew A Brown; Alan James; Philip J Thompson; Craig Pennell; Nicholas G Martin; David M Evans; David A Hinds; John L Hopper; Australian Asthma Genetics Consortium Collaborators

doi:10.1016/j.jaci.2013.10.030

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

J Allergy Clin Immunol. 2014 Jun;133(6):1564-71. doi: 10.1016/j.jaci.2013.10.030. Epub 2013 Dec 31.

Authors

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

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: [email protected].
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: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Adult
Alleles
Asthma / complications
Asthma / diagnosis*
Asthma / genetics*
Female
Gene Frequency
Genetic Variation*
Genome-Wide Association Study*
Humans
Lectins, C-Type / genetics
Linkage Disequilibrium
Male
Middle Aged
Monosaccharide Transport Proteins / genetics
Odds Ratio
Phenotype*
Polymorphism, Single Nucleotide
Quantitative Trait Loci*
Repressor Proteins / genetics
Rhinitis, Allergic, Seasonal / complications
Rhinitis, Allergic, Seasonal / diagnosis*
Rhinitis, Allergic, Seasonal / genetics*
Young Adult

Substances

CLEC16A protein, human
Lectins, C-Type
Monosaccharide Transport Proteins
Repressor Proteins
ZBTB10 protein, human

Abstract

Publication types

MeSH terms

Substances

Grants and funding