Universität zu Köln

Nieuwenhuis, M. A., Siedlinski, M., van den Berge, M., Granell, R., Li, X., Niens, M., van der Vlies, P., Altmueller, J., Nuernberg, P., Kerkhof, M., van Schayck, O. C., Riemersma, R. A., van der Molen, T., de Monchy, J. G., Bosse, Y., Sandford, A., Bruijnzeel-Koomen, C. A., Gerth van Wijk, R., ten Hacken, N. H., Timens, W., Boezen, H. M., Henderson, J., Kabesch, M., Vonk, J. M., Postma, D. S. and Koppelman, G. H. (2016). Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma. Allergy, 71 (12). S. 1712 - 1721. HOBOKEN: WILEY-BLACKWELL. ISSN 1398-9995

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Abstract

BackgroundGenomewide 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. MethodsA 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. ResultsA 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. ConclusionsCombining 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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Nieuwenhuis, M. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Siedlinski, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van den Berge, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Granell, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Li, X. UNSPECIFIED UNSPECIFIED UNSPECIFIED Niens, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Vlies, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Altmueller, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kerkhof, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED van Schayck, O. C. UNSPECIFIED UNSPECIFIED UNSPECIFIED Riemersma, R. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED van der Molen, T. UNSPECIFIED UNSPECIFIED UNSPECIFIED de Monchy, J. G. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bosse, Y. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sandford, A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Bruijnzeel-Koomen, C. A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gerth van Wijk, R. UNSPECIFIED UNSPECIFIED UNSPECIFIED ten Hacken, N. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Timens, W. UNSPECIFIED UNSPECIFIED UNSPECIFIED Boezen, H. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Henderson, J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Kabesch, M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Vonk, J. M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Postma, D. S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Koppelman, G. H. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-254588
DOI:	10.1111/all.12990
Journal or Publication Title:	Allergy
Volume:	71
Number:	12
Page Range:	S. 1712 - 1721
Date:	2016
Publisher:	WILEY-BLACKWELL
Place of Publication:	HOBOKEN
ISSN:	1398-9995
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language WIDE ASSOCIATION; SUSCEPTIBILITY LOCI; CANDIDATE GENE; POLYMORPHISMS; CHILDREN; IDENTIFICATION; METAANALYSIS; FLUTICASONE; POPULATION; ALLERGY Multiple languages Allergy; Immunology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/25458