Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

M A Nieuwenhuis; M Siedlinski; M van den Berge; R Granell; X Li; M Niens; P van der Vlies; J Altmüller; P Nürnberg; M Kerkhof; O C van Schayck; R A Riemersma; T van der Molen; J G de Monchy; Y Bossé; A Sandford; C A Bruijnzeel-Koomen; R Gerth van Wijk; N H Ten Hacken; W Timens; H M Boezen; J Henderson; M Kabesch; J M Vonk; D S Postma; G H Koppelman

doi:10.1111/all.12990

Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

Allergy. 2016 Dec;71(12):1712-1720. doi: 10.1111/all.12990. Epub 2016 Aug 22.

Authors

M A Nieuwenhuis^{1

2}, M Siedlinski^{2

3}, M van den Berge^{1

2}, R Granell⁴, X Li⁵, M Niens⁶, P van der Vlies⁶, J Altmüller⁷, P Nürnberg⁷, M Kerkhof^{2

3}, O C van Schayck⁸, R A Riemersma^{2

9}, T van der Molen^{2

9}, J G de Monchy^{2

10}, Y Bossé¹¹, A Sandford¹², C A Bruijnzeel-Koomen¹³, R Gerth van Wijk¹⁴, N H Ten Hacken^{1

2}, W Timens^{2

15}, H M Boezen^{2

3}, J Henderson⁴, M Kabesch¹⁶, J M Vonk^{2

3}, D S Postma^{1

2}, G H Koppelman^{2

17}

Affiliations

¹ Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
² Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
³ Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁴ School of Social and Community Medicine, University of Bristol, Bristol, UK.
⁵ Wake Forest School of Medicine, Center for Genomics and Personalized Medicine Research and the Section on Pulmonary, Critical Care, Allergy and Immunologic Disease, Winston-Salem, NC, USA.
⁶ Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
⁷ Cologne Center for Genomics (CCG), Universität zu Köln, Köln, Germany.
⁸ Department of General Practice, CAPHRI, MUMC+, Maastricht, the Netherlands.
⁹ Department of General Practice, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹⁰ Department Allergology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹¹ Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada.
¹² James Hogg Research Laboratory, St Paul's Hospital, The University of British Columbia, Vancouver, Canada.
¹³ Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht, the Netherlands.
¹⁴ Department of Allergology, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.
¹⁵ Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
¹⁶ Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
¹⁷ Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.

Abstract

Background: Genomewide association studies (GWASs) of asthma have identified single-nucleotide polymorphisms (SNPs) that modestly increase the risk for asthma. This could be due to phenotypic heterogeneity of asthma. Bronchial hyperresponsiveness (BHR) is a phenotypic hallmark of asthma. We aim to identify susceptibility genes for asthma combined with BHR and analyse the presence of cis-eQTLs among replicated SNPs. Secondly, we compare the genetic association of SNPs previously associated with (doctor's diagnosed) asthma to our GWAS of asthma with BHR.

Methods: A GWAS was performed in 920 asthmatics with BHR and 980 controls. Top SNPs of our GWAS were analysed in four replication cohorts, and lung cis-eQTL analysis was performed on replicated SNPs. We investigated association of SNPs previously associated with asthma in our data.

Results: A total of 368 SNPs were followed up for replication. Six SNPs in genes encoding ABI3BP, NAF1, MICA and the 17q21 locus replicated in one or more cohorts, with one locus (17q21) achieving genomewide significance after meta-analysis. Five of 6 replicated SNPs regulated 35 gene transcripts in whole lung. Eight of 20 asthma-associated SNPs from previous GWAS were significantly associated with asthma and BHR. Three SNPs, in IL-33 and GSDMB, showed larger effect sizes in our data compared to published literature.

Conclusions: Combining GWAS with subsequent lung eQTL analysis revealed disease-associated SNPs regulating lung mRNA expression levels of potential new asthma genes. Adding BHR to the asthma definition does not lead to an overall larger genetic effect size than analysing (doctor's diagnosed) asthma.

Keywords: asthma; bronchial hyperresponsiveness; gene expression; genetics; genomewide association studies.

Publication types

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

MeSH terms

Alleles
Asthma / epidemiology
Asthma / genetics*
Case-Control Studies
Chromosome Mapping
Female
Genetic Association Studies
Genetic Predisposition to Disease*
Genome-Wide Association Study*
Genotype
Humans
Lung / immunology
Lung / metabolism*
Male
Meta-Analysis as Topic
Netherlands / epidemiology
Phenotype
Polymorphism, Single Nucleotide
Population Surveillance
Quantitative Trait Loci*

Abstract

Publication types

MeSH terms

Grants and funding