title: Combining genomewide association study and lung eQTL analysis provides evidence for novel genes associated with asthma.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: M A
authors.initials: MA
authors.lastname: Nieuwenhuis
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Siedlinski
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: van den Berge
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: R
authors.initials: R
authors.lastname: Granell
authors.affiliation: 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.
authors.forename: X
authors.initials: X
authors.lastname: Li
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Niens
authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: P
authors.initials: P
authors.lastname: van der Vlies
authors.affiliation: Cologne Center for Genomics (CCG), Universität zu Köln, Köln, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Altmüller
authors.affiliation: Cologne Center for Genomics (CCG), Universität zu Köln, Köln, Germany.
authors.forename: P
authors.initials: P
authors.lastname: Nürnberg
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: M
authors.initials: M
authors.lastname: Kerkhof
authors.affiliation: Department of General Practice, CAPHRI, MUMC+, Maastricht, the Netherlands.
authors.forename: O C
authors.initials: OC
authors.lastname: van Schayck
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of General Practice, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: R A
authors.initials: RA
authors.lastname: Riemersma
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of General Practice, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: van der Molen
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department Allergology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: J G
authors.initials: JG
authors.lastname: de Monchy
authors.affiliation: Department of Molecular Medicine, Institut Universitaire de Cardiologie et de Pneumologie de Québec, Laval University, Québec, Canada.
authors.forename: Y
authors.initials: Y
authors.lastname: Bossé
authors.affiliation: James Hogg Research Laboratory, St Paul's Hospital, The University of British Columbia, Vancouver, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Sandford
authors.affiliation: Department of Dermatology and Allergology, University Medical Center Utrecht, Utrecht, the Netherlands.
authors.forename: C A
authors.initials: CA
authors.lastname: Bruijnzeel-Koomen
authors.affiliation: Department of Allergology, Erasmus Medical Centre Rotterdam, Rotterdam, the Netherlands.
authors.forename: R
authors.initials: R
authors.lastname: Gerth van Wijk
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: N H
authors.initials: NH
authors.lastname: Ten Hacken
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Pathology and Medical Biology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: W
authors.initials: W
authors.lastname: Timens
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: H M
authors.initials: HM
authors.lastname: Boezen
authors.affiliation: School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: J
authors.initials: J
authors.lastname: Henderson
authors.affiliation: Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Kabesch
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Epidemiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: J M
authors.initials: JM
authors.lastname: Vonk
authors.affiliation: Department of Pulmonary Diseases, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: D S
authors.initials: DS
authors.lastname: Postma
authors.affiliation: Groningen Research Institute for Asthma and COPD (GRIAC), University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.|Department of Pediatric Pulmonology and Pediatric Allergology, Beatrix Children's Hospital, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands.
authors.forename: G H
authors.initials: GH
authors.lastname: Koppelman
mesh_terms: D000483:Alleles; D001249:Asthma / Q000453:epidemiology / Q000235:genetics*; D016022:Case-Control Studies; D002874:Chromosome Mapping; D005260:Female; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D005838:Genotype; D006801:Humans; D008168:Lung / Q000276:immunology / Q000378:metabolism*; D008297:Male; D015201:Meta-Analysis as Topic; D009426:Netherlands / Q000453:epidemiology; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D040641:Quantitative Trait Loci
keywords: asthma; bronchial hyperresponsiveness; gene expression; genetics; genomewide association studies