Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: Sakornsakolpat, Phuwanat, Morrow, Jarrett D., Castaldi, Peter J., Hersh, Craig P., Bossé, Yohan, Silverman, Edwin K., Manichaikul, Ani, Cho, Michael H.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
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
_version_ 1783308445402791936
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
work_keys_str_mv AT sakornsakolpatphuwanat integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT morrowjarrettd integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT castaldipeterj integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT hershcraigp integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT bosseyohan integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT silvermanedwink integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT manichaikulani integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema
AT chomichaelh integrativegenomicsidentifiesnewgenesassociatedwithseverecopdandemphysema