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Integrative genomics identifies new genes associated with severe COPD and emphysema
BACKGROUND: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that...
Autores principales: | , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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BioMed Central
2018
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863845/ https://www.ncbi.nlm.nih.gov/pubmed/29566699 http://dx.doi.org/10.1186/s12931-018-0744-9 |
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author | Sakornsakolpat, Phuwanat Morrow, Jarrett D. Castaldi, Peter J. Hersh, Craig P. Bossé, Yohan Silverman, Edwin K. Manichaikul, Ani Cho, Michael H. |
author_facet | Sakornsakolpat, Phuwanat Morrow, Jarrett D. Castaldi, Peter J. Hersh, Craig P. Bossé, Yohan Silverman, Edwin K. Manichaikul, Ani Cho, Michael H. |
author_sort | Sakornsakolpat, Phuwanat |
collection | PubMed |
description | BACKGROUND: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes. METHODS: We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization. RESULTS: We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation. CONCLUSIONS: An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci. TRIAL REGISTRATION: NCT00608764, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-018-0744-9) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5863845 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2018 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-58638452018-03-27 Integrative genomics identifies new genes associated with severe COPD and emphysema Sakornsakolpat, Phuwanat Morrow, Jarrett D. Castaldi, Peter J. Hersh, Craig P. Bossé, Yohan Silverman, Edwin K. Manichaikul, Ani Cho, Michael H. Respir Res Research BACKGROUND: Genome-wide association studies have identified several genetic risk loci for severe chronic obstructive pulmonary disease (COPD) and emphysema. However, these studies do not fully explain disease heritability and in most cases, fail to implicate specific genes. Integrative methods that combine gene expression data with GWAS can provide more power in discovering disease-associated genes and give mechanistic insight into regulated genes. METHODS: We applied a recently described method that imputes gene expression using reference transcriptome data to genome-wide association studies for two phenotypes (severe COPD and quantitative emphysema) and blood and lung tissue gene expression datasets. We further tested the potential causality of individual genes using multi-variant colocalization. RESULTS: We identified seven genes significantly associated with severe COPD, and five genes significantly associated with quantitative emphysema in whole blood or lung. We validated results in independent transcriptome databases and confirmed colocalization signals for PSMA4, EGLN2, WNT3, DCBLD1, and LILRA3. Three of these genes were not located within previously reported GWAS loci for either phenotype. We also identified genetically driven pathways, including those related to immune regulation. CONCLUSIONS: An integrative analysis of GWAS and gene expression identified novel associations with severe COPD and quantitative emphysema, and also suggested disease-associated genes in known COPD susceptibility loci. TRIAL REGISTRATION: NCT00608764, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: November 2007, Date Registered: January 28, 2008 (retrospectively registered); NCT00292552, Registry: ClinicalTrials.gov, Date of Enrollment of First Participant: December 2005, Date Registered: February 14, 2006 (retrospectively registered). ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12931-018-0744-9) contains supplementary material, which is available to authorized users. BioMed Central 2018-03-22 2018 /pmc/articles/PMC5863845/ /pubmed/29566699 http://dx.doi.org/10.1186/s12931-018-0744-9 Text en © The Author(s). 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Sakornsakolpat, Phuwanat Morrow, Jarrett D. Castaldi, Peter J. Hersh, Craig P. Bossé, Yohan Silverman, Edwin K. Manichaikul, Ani Cho, Michael H. Integrative genomics identifies new genes associated with severe COPD and emphysema |
title | Integrative genomics identifies new genes associated with severe COPD and emphysema |
title_full | Integrative genomics identifies new genes associated with severe COPD and emphysema |
title_fullStr | Integrative genomics identifies new genes associated with severe COPD and emphysema |
title_full_unstemmed | Integrative genomics identifies new genes associated with severe COPD and emphysema |
title_short | Integrative genomics identifies new genes associated with severe COPD and emphysema |
title_sort | integrative genomics identifies new genes associated with severe copd and emphysema |
topic | Research |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5863845/ https://www.ncbi.nlm.nih.gov/pubmed/29566699 http://dx.doi.org/10.1186/s12931-018-0744-9 |
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