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. Altmueller; P. Nuernberg; M. Kerkhof; O. C. van Schayck; R. A. Riemersma; T. van der Molen; J. G. de Monchy; Y. Bosse; 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

M. A. Nieuwenhuis, M. Siedlinski, M. van den Berge, R. Granell, X. Li, M. Niens, P. van der Vlies, J. Altmueller, P. Nuernberg, M. Kerkhof, O. C. van Schayck, R. A. Riemersma, T. van der Molen, J. G. de Monchy, Y. Bosse, A. Sandford, C. A. Bruijnzeel-Koomen, R. Gerth van Wijk, N. H. ten Hacken, W. TimensH. M. Boezen, J. Henderson, M. Kabesch, J. M. Vonk, D. S. Postma, G. H. Koppelman^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

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. 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.

Original language	English
Pages (from-to)	1712-1720
Journal	Allergy
Volume	71
Issue number	12
DOIs	https://doi.org/10.1111/all.12990
Publication status	Published - Dec 2016

Keywords

asthma
bronchial hyperresponsiveness
gene expression
genetics
genomewide association studies

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10.1111/all.12990

Cite this

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., ... Koppelman, G. H. (2016). Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma. Allergy, 71(12), 1712-1720. https://doi.org/10.1111/all.12990

@article{87aa77dd2f194c76a8c44a51462ab1e8,

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

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. 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.",

keywords = "asthma, bronchial hyperresponsiveness, gene expression, genetics, genomewide association studies",

author = "Nieuwenhuis, {M. A.} and M. Siedlinski and {van den Berge}, M. and R. Granell and X. Li and M. Niens and {van der Vlies}, P. and J. Altmueller and P. Nuernberg and M. Kerkhof and {van Schayck}, {O. C.} and Riemersma, {R. A.} and {van der Molen}, T. and {de Monchy}, {J. G.} and Y. Bosse and A. Sandford and Bruijnzeel-Koomen, {C. A.} and {Gerth van Wijk}, R. and {ten Hacken}, {N. H.} and W. Timens and Boezen, {H. M.} and J. Henderson and M. Kabesch and Vonk, {J. M.} and Postma, {D. S.} and Koppelman, {G. H.}",

year = "2016",

month = dec,

doi = "10.1111/all.12990",

language = "English",

volume = "71",

pages = "1712--1720",

journal = "Allergy",

issn = "0105-4538",

publisher = "Wiley-Blackwell",

number = "12",

}

Nieuwenhuis, MA, Siedlinski, M, van den Berge, M, Granell, R, Li, X, Niens, M, van der Vlies, P, Altmueller, J, Nuernberg, P, Kerkhof, M, van Schayck, OC, Riemersma, RA, van der Molen, T, de Monchy, JG, Bosse, Y, Sandford, A, Bruijnzeel-Koomen, CA, Gerth van Wijk, R, ten Hacken, NH, Timens, W, Boezen, HM, Henderson, J, Kabesch, M, Vonk, JM, Postma, DS & Koppelman, GH 2016, 'Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma', Allergy, vol. 71, no. 12, pp. 1712-1720. https://doi.org/10.1111/all.12990

TY - JOUR

T1 - Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma

AU - Nieuwenhuis, M. A.

AU - Siedlinski, M.

AU - van den Berge, M.

AU - Granell, R.

AU - Li, X.

AU - Niens, M.

AU - van der Vlies, P.

AU - Altmueller, J.

AU - Nuernberg, P.

AU - Kerkhof, M.

AU - van Schayck, O. C.

AU - Riemersma, R. A.

AU - van der Molen, T.

AU - de Monchy, J. G.

AU - Bosse, Y.

AU - Sandford, A.

AU - Bruijnzeel-Koomen, C. A.

AU - Gerth van Wijk, R.

AU - ten Hacken, N. H.

AU - Timens, W.

AU - Boezen, H. M.

AU - Henderson, J.

AU - Kabesch, M.

AU - Vonk, J. M.

AU - Postma, D. S.

AU - Koppelman, G. H.

PY - 2016/12

Y1 - 2016/12

N2 - 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. 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.

AB - 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. 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.

KW - asthma

KW - bronchial hyperresponsiveness

KW - gene expression

KW - genetics

KW - genomewide association studies

U2 - 10.1111/all.12990

DO - 10.1111/all.12990

M3 - Article

C2 - 27439200

SN - 0105-4538

VL - 71

SP - 1712

EP - 1720

JO - Allergy

JF - Allergy

IS - 12

ER -