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

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. TimensH. M. Boezen, J. Henderson, M. Kabesch, J. M. Vonk, D. S. Postma, G. H. Koppelman^*

^*Corresponding author for this work

Bristol Medical School (PHS)

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

45 Citations (Scopus)

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.

Original language	English
Pages (from-to)	1712-1720
Number of pages	9
Journal	Allergy
Volume	71
Issue number	12
Early online date	22 Aug 2016
DOIs	https://doi.org/10.1111/all.12990
Publication status	Published - Dec 2016

Keywords

asthma
bronchial hyperresponsiveness
gene expression
genomewide association studies
Genetics

Access to Document

10.1111/all.12990

Handle.net

Persistent link

Cite this

Nieuwenhuis, M. A., Siedlinski, M., van den Berge, M., Granell, R., Li, X., Niens, M., van der Vlies, P., Altmüller, J., Nürnberg, P., Kerkhof, M., van Schayck, O. C., Riemersma, R. A., van der Molen, T., de Monchy, J. G., Bossé, 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{1c04f1cf182d48189280d6e0225af774,

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

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.",

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

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. Altm{\"u}ller and P. N{\"u}rnberg and M. Kerkhof and {van Schayck}, {O. C.} and Riemersma, {R. A.} and {van der Molen}, T. and {de Monchy}, {J. G.} and Y. Boss{\'e} 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, Altmüller, J, Nürnberg, P, Kerkhof, M, van Schayck, OC, Riemersma, RA, van der Molen, T, de Monchy, JG, Bossé, 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 - Altmüller, J.

AU - Nürnberg, P.

AU - Kerkhof, M.

AU - van Schayck, O. C.

AU - Riemersma, R. A.

AU - van der Molen, T.

AU - de Monchy, J. G.

AU - Bossé, 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 - 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.

AB - 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.

KW - asthma

KW - bronchial hyperresponsiveness

KW - gene expression

KW - genomewide association studies

KW - Genetics

UR - http://www.scopus.com/inward/record.url?scp=84994528769&partnerID=8YFLogxK

U2 - 10.1111/all.12990

DO - 10.1111/all.12990

M3 - Article (Academic Journal)

C2 - 27439200

AN - SCOPUS:84994528769

SN - 0105-4538

VL - 71

SP - 1712

EP - 1720

JO - Allergy

JF - Allergy

IS - 12

ER -

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

Abstract

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

THE NATURAL HISTORY OF ASTHMA AND WHEEZING ILLNESSES FROM BIRTH TO ADOLESCENCE: DETERMINANTS OF THE REMISSION OF ASTHMA

EXTENSION OF RD1321 VIA IOP.

Cite this

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

Abstract

Keywords

Access to Document

Handle.net

Other files and links

Fingerprint

Projects

THE NATURAL HISTORY OF ASTHMA AND WHEEZING ILLNESSES FROM BIRTH TO ADOLESCENCE: DETERMINANTS OF THE REMISSION OF ASTHMA

EXTENSION OF RD1321 VIA IOP.

Cite this