|
|
| PMID |
|
|
| 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 |
|
|
| 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 |
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| PUBLICATIONTYPE TEXT |
| JOURNAL ARTICLE |
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| COMMENTS AND CORRECTIONS |
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| GRANTS |
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| GENERAL NOTE |
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| KEYWORDS |
|
| KEYWORD |
| AOAH |
| CLK3 |
| EUGENE |
| Inflammation |
| PrediXcan |
| TWAS |
| UDP-glucose |
| VEGAS |
| ZNF707 |
| eQTL |
| obesity |
| predisposition |
| transcriptome |
|
| MESH HEADINGS |
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|
| SUPPLEMENTARY MESH |
|
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| GENE SYMBOLS |
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| CHEMICALS |
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| OTHER ID's |
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