title: Gene-based analysis of regulatory variants identifies 4 putative novel asthma risk genes related to nucleotide synthesis and signaling.
abstract: BACKGROUND
  Hundreds of genetic variants are thought to contribute to variation in asthma risk by modulating gene expression. Methods that increase the power of genome-wide association studies (GWASs) to identify risk-associated variants are needed.
  
  
  OBJECTIVE
  We sought to develop a method that aggregates the evidence for association with disease risk across expression quantitative trait loci (eQTLs) of a gene and use this approach to identify asthma risk genes.
  
  
  METHODS
  We developed a gene-based test and software package called EUGENE that (1) is applicable to GWAS summary statistics; (2) considers both cis- and trans-eQTLs; (3) incorporates eQTLs identified in different tissues; and (4) uses simulations to account for multiple testing. We applied this approach to 2 published asthma GWASs (combined n = 46,044) and used mouse studies to provide initial functional insights into 2 genes with novel genetic associations.
  
  
  RESULTS
  We tested the association between asthma and 17,190 genes that were found to have cis- and/or trans-eQTLs across 16 published eQTL studies. At an empirical FDR of 5%, 48 genes were associated with asthma risk. Of these, for 37, the association was driven by eQTLs located in established risk loci for allergic disease, including 6 genes not previously implicated in disease cause (eg, LIMS1, TINF2, and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with 4 of these replicated in an independent GWAS: B4GALT3, USMG5, P2RY13, and P2RY14, which are genes involved in nucleotide synthesis or nucleotide-dependent cell activation. In mouse studies, P2ry13 and P2ry14-purinergic receptors activated by adenosine 5-diphosphate and UDP-sugars, respectively-were upregulated after allergen challenge, notably in airway epithelial cells, eosinophils, and neutrophils. Intranasal exposure with receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.
  
  
  CONCLUSIONS
  We identified novel associations between asthma and eQTLs for 4 genes related to nucleotide synthesis/signaling and demonstrated the power of gene-based analyses of GWASs.
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
authors.forename: Manuel A R
authors.initials: MA
authors.lastname: Ferreira
authors.affiliation: Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Jansen
authors.affiliation: Department of Biological Psychology, Vrije University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Gonneke
authors.initials: G
authors.lastname: Willemsen
authors.affiliation: Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Brenda
authors.initials: B
authors.lastname: Penninx
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Bain
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Cristina T
authors.initials: CT
authors.lastname: Vicente
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Joana A
authors.initials: JA
authors.lastname: Revez
authors.affiliation: Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: Melanie C
authors.initials: MC
authors.lastname: Matheson
authors.affiliation: PathWest Laboratory Medicine of Western Australia, Nedlands, Australia; School of Population Health, University of Western Australia, Nedlands, Australia; School of Pathology and Laboratory Medicine, University of Western Australia, Crawley, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands, Australia.
authors.forename: Jennie
authors.initials: J
authors.lastname: Hui
authors.affiliation: 23andMe Inc, Mountain View, Calif.
authors.forename: Joyce Y
authors.initials: JY
authors.lastname: Tung
authors.affiliation: Institute for Respiratory Health, Harry Perkins Institute of Medical Research, Nedlands, Australia.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Baltic
authors.affiliation: School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Subiaco, Australia.
authors.forename: Peter
authors.initials: P
authors.lastname: Le Souëf
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Grant W
authors.initials: GW
authors.lastname: Montgomery
authors.affiliation: QIMR Berghofer Medical Research Institute, Brisbane, Australia.
authors.forename: Nicholas G
authors.initials: NG
authors.lastname: Martin
authors.affiliation: Respiratory Medicine, Murdoch Children's Research Institute, Melbourne, Australia.
authors.forename: Colin F
authors.initials: CF
authors.lastname: Robertson
authors.affiliation: Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia; Department of Pulmonary Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Nedlands, Australia.
authors.forename: Alan
authors.initials: A
authors.lastname: James
authors.affiliation: Institute for Respiratory Health, Harry Perkins Institute of Medical Research, Nedlands, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands, Australia.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Thompson
authors.affiliation: Department of Biological Psychology, Vrije University Amsterdam, Amsterdam, The Netherlands.
authors.forename: Dorret I
authors.initials: DI
authors.lastname: Boomsma
authors.affiliation: Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Australia.
authors.forename: John L
authors.initials: JL
authors.lastname: Hopper
authors.affiliation: 23andMe Inc, Mountain View, Calif.
authors.forename: David A
authors.initials: DA
authors.lastname: Hinds
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Rhiannon B
authors.initials: RB
authors.lastname: Werder
authors.affiliation: School of Biomedical Sciences, University of Queensland, Brisbane, Australia.
authors.forename: Simon
authors.initials: S
authors.lastname: Phipps
mesh_terms: D000818:Animals; D001249:Asthma / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D014644:Genetic Variation / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D025261:Mitochondrial Proton-Translocating ATPases / Q000235:genetics; D009711:Nucleotides / Q000096:biosynthesis / Q000235:genetics*; D040641:Quantitative Trait Loci / Q000235:genetics; D018048:Receptors, Purinergic P2 / Q000235:genetics; D058470:Receptors, Purinergic P2Y / Q000235:genetics; D012984:Software
chemical_list: D025261:Mitochondrial Proton-Translocating ATPases; D009711:Nucleotides; D018048:Receptors, Purinergic P2; D058470:Receptors, Purinergic P2Y; C000606721:ATP5MK protein, human; C440036:P2RY13 protein, human; C486689:P2ry13 protein, mouse; C509795:P2ry14 protein, mouse; C518528:P2Y14 receptor, human
keywords: AOAH; CLK3; EUGENE; Inflammation; P2Y13; P2Y14; PrediXcan; TWAS; UDP-glucose; VEGAS; ZNF707; expression quantitative trait locus; obesity; predisposition; transcriptome