Integrative genomics identifies new genes associated with severe COPD and emphysema

Phuwanat Sakornsakolpat, Jarrett D Morrow, Peter J Castaldi, Craig P Hersh, Yohan Bossé, Edwin K Silverman, Ani Manichaikul, Michael H Cho, Phuwanat Sakornsakolpat, Jarrett D Morrow, Peter J Castaldi, Craig P Hersh, Yohan Bossé, Edwin K Silverman, Ani Manichaikul, Michael H Cho

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.

Conflict of interest statement

Ethics approval and consent to participate

Local institutional review boards provided ethical approval for the clinical centers. Written informed consent was obtained in all studies.

Consent for publication

Not applicable

Competing interests

The authors declare that they have no competing interests.

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Fig. 1
Fig. 1
Summary of analyses. First, we discovered transcriptome-disease associations (predicted gene expression-disease) using reference data from DGN-Blood and GTEx-Lung. Then, we validated these associations using another set of reference data (GTEx-Blood and Lung-eQTL Consortium). Finally, we confirmed the transcriptome-disease associations using colocalization analysis. COPD = chronic obstructive pulmonary disease; DGN = Depression Gene Network; GTEx = Genotype-Tissue Expression project; Perc15 HU at 15th percentile of the density histogram; severe COPD is defined as FEV1 < 50% predicted and FEV1/FVC < 0.7
Fig. 2
Fig. 2
Manhattan plots of associations of imputed gene expression and phenotypes (severe COPD in the upper panel; %LAA-950 and Perc15 in the lower panel). Color indicates phenotypes and shape indicates tissue (see figure legend)
Fig. 3
Fig. 3
Regional association plots within 50 kb of WNT3. GWAS of severe COPD and lung eQTL are shown in the upper panel. Chromatin states and epigenomic marks of normal human lung fibroblasts are shown in the lower panel (see Additional file 1: Supplementary Methods)

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