Genetic Epidemiology, Psychiatric Genetics, Asthma Genetics and Statistical Genetics Laboratories investigate the pattern of disease in families, particularly identical and non-identical twins, to assess the relative importance of genes and environment in a variety of important health problems.
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PMID
27554816
TITLE
Gene-based analysis of regulatory variants identifies four putative novel asthma risk genes related to nucleotide synthesis and signaling.
ABSTRACT
BACKGROUND NlmCategory: 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 (GWAS) to identify risk-associated variants are needed.
OBJECTIVE NlmCategory: OBJECTIVE
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 NlmCategory: 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 two published asthma GWAS (combined N=46,044) and used mouse studies to provide initial functional insights into two genes with novel genetic associations.
RESULTS NlmCategory: RESULTS
We tested the association between asthma and 17,190 genes which were found to have cis-and/or trans-eQTLs across 16 published eQTL studies. At an empirical false discovery rate 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 six genes not previously implicated in disease aetiology (eg. LIMS1, TINF2 and SAFB). The remaining 11 significant genes represent potential novel genetic associations with asthma. The association with four 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 ADP and UDP-sugars, respectively - were up-regulated after allergen challenge, notably in airway epithelial cells, eosinophils and neutrophils. Intranasal exposure with the receptor agonists induced the release of IL-33 and subsequent eosinophil infiltration into the lungs.
CONCLUSION NlmCategory: CONCLUSIONS
We identified novel associations between asthma and eQTLs for four genes related to nucleotide synthesis/signaling, and demonstrate the power of gene-based analyses of GWAS.
Copyright 2016. Published by Elsevier Inc.
DATE PUBLISHED
2016 Aug 20
HISTORY
PUBSTATUS PUBSTATUSDATE
received 2016/02/19
revised 2016/07/08
accepted 2016/07/12
entrez 2016/08/25 06:00
pubmed 2016/08/25 06:00
medline 2016/08/25 06:00
AUTHORS
NAME COLLECTIVENAME LASTNAME FORENAME INITIALS AFFILIATION AFFILIATIONINFO
Ferreira MA Ferreira Manuel A R MA QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia. Electronic address: manuel.ferreira@qimrberghofer.edu.au.
Jansen R Jansen Rick R Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Willemsen G Willemsen Gonneke G Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
Penninx B Penninx Brenda B Department of Psychiatry, VU University Medical Center, Amsterdam, The Netherlands.
Bain LM Bain Lisa M LM QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia.
Vicente CT Vicente Cristina T CT QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia.
Revez JA Revez Joana A JA QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia.
Matheson MC Matheson Melanie C MC Melbourne School of Population and Global Health, The University of Melbourne, Melbourne 3010, Australia.
Hui J Hui Jennie J PathWest Laboratory Medicine of Western Australia (WA), Nedlands 6009, Australia; School of Population Health, The University of WA, Nedlands 6009, Australia; School of Pathology and Laboratory Medicine, The University of WA, Crawley 6009, Australia; Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands 6009, Australia.
Tung JY Tung Joyce Y JY 23andMe, Mountain View, California 94041, USA.
Baltic S Baltic Svetlana S Institute for Respiratory Health, Harry Perkins Institute of Medical Research, Nedlands 6009, Australia.
Le Souëf P Le Souëf Peter P School of Paediatrics and Child Health, Princess Margaret Hospital for Children, Subiaco 6008, Australia.
AAGC collaborators
Montgomery GW Montgomery Grant W GW QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia.
Martin NG Martin Nicholas G NG QIMR Berghofer Medical Research Institute, Brisbane 4029, Australia.
Robertson CF Robertson Colin F CF Respiratory Medicine, Murdoch Children's Research Institute, Melbourne 3052, Australia.
James A James Alan A Busselton Population Medical Research Foundation, Sir Charles Gairdner Hospital, Nedlands 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands 6009, Australia; Department of Pulmonary Physiology and Sleep Medicine, West Australian Sleep Disorders Research Institute, Nedlands 6009, Australia.
Thompson PJ Thompson Philip J PJ Institute for Respiratory Health, Harry Perkins Institute of Medical Research, Nedlands 6009, Australia; School of Medicine and Pharmacology, University of Western Australia, Nedlands 6009, Australia.
Boomsma DI Boomsma Dorret I DI Department of Biological Psychology, VU University Amsterdam, Amsterdam, The Netherlands.
Hopper JL Hopper John L JL Melbourne School of Population and Global Health, The University of Melbourne, Melbourne 3010, Australia.
Hinds DA Hinds David A DA 23andMe, Mountain View, California 94041, USA.
Werder RB Werder Rhiannon B RB School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia.
Phipps S Phipps Simon S School of Biomedical Sciences, The University of Queensland, Brisbane 4072, Australia.
INVESTIGATORS
JOURNAL
VOLUME:
ISSUE:
TITLE: The Journal of allergy and clinical immunology
ISOABBREVIATION: J. Allergy Clin. Immunol.
YEAR: 2016
MONTH: Aug
DAY: 20
MEDLINEDATE:
SEASON:
CITEDMEDIUM: Internet
ISSN: 1097-6825
ISSNTYPE: Electronic
MEDLINE JOURNAL
MEDLINETA: J Allergy Clin Immunol
COUNTRY: United States
ISSNLINKING: 0091-6749
NLMUNIQUEID: 1275002
PUBLICATION TYPE
PUBLICATIONTYPE TEXT
JOURNAL ARTICLE
COMMENTS AND CORRECTIONS
GRANTS
GENERAL NOTE
KEYWORDS
KEYWORD
AOAH
CLK3
EUGENE
Inflammation
PrediXcan
TWAS
UDP-glucose
VEGAS
ZNF707
eQTL
obesity
predisposition
transcriptome
MESH HEADINGS
SUPPLEMENTARY MESH
GENE SYMBOLS
CHEMICALS
OTHER ID's