Format

Send to

Choose Destination
Respir Res. 2018 Mar 22;19(1):46. doi: 10.1186/s12931-018-0744-9.

Integrative genomics identifies new genes associated with severe COPD and emphysema.

Author information

1
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA.
2
Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
3
Division of General Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA.
4
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA.
5
Department of Molecular Medicine, Institut universitaire de cardiologie et de pneumologie de Québec, Laval University, Quebec, Canada.
6
Department of Public Health Sciences, Center for Public Health Genomics and Biostatistics Section, University of Virginia, Charlottesville, VA, USA.
7
Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA. remhc@channing.harvard.edu.
8
Division of Pulmonary and Critical Care Medicine, Department of Medicine, Brigham and Women's Hospital, 181 Longwood Avenue, Room 451, Boston, MA, 02115, USA. remhc@channing.harvard.edu.

Abstract

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).

KEYWORDS:

Chronic obstructive pulmonary disease; Emphysema; Gene expression; Genome-wide association studies

PMID:
29566699
PMCID:
PMC5863845
DOI:
10.1186/s12931-018-0744-9
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Secondary source ID, Grant support

Publication types

MeSH terms

Secondary source ID

Grant support

Supplemental Content

Full text links

Icon for BioMed Central Icon for PubMed Central
Loading ...
Support Center