Dataset Information

NHLBI TOPMed: Boston Early-Onset COPD Study in the TOPMed Program

ABSTRACT:

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death in the United States and the only leading cause of death that is steadily increasing in frequency. This project collected a set of extended pedigrees ascertained through subjects with severe, early-onset COPD. This study has enrolled subjects with severe COPD (forced expiratory volume in one second (FEV1) < 40% predicted) at an early age (< 53 years) without alpha-1 antitrypsin deficiency (a known Mendelian risk factor for COPD). Extended pedigrees are enrolled, primarily in New England, although some more geographically distant subjects have been included. This study has been used for epidemiological studies, familial aggregation analysis, linkage analysis, and candidate gene association analysis. Approximately 80 of the severe, early-onset COPD probands will undergo whole genome sequencing in this project with sequencing data available through dbGaP.

This third study release makes available VCF files derived from sequence aligned to genome build 38, in addition to those aligned to build 37 and available through study version 1. The samples in the b38 vs b37 VCF may also differ.

PROVIDER: phs000946 | dbGaP |

SECONDARY ACCESSION(S): PRJNA288740PRJNA288739

REPOSITORIES: dbGaP

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Project description:Multiple gene expression studies have been performed in lung or airway tissues from subjects with chronic obstructive pulmonary disease (COPD). However, in comparison to genome-wide association studies (GWAS), there has been poor replication across these studies. We sought to perform gene expression profiling on a large sample of severe COPD cases and control smokers and use network methods to identify interacting genes and pathways. We collected surgically-resected lung tissue samples from subjects with severe COPD and controls with normal lung function; all subjects were former smokers. Gene expression profiling on homogenized lung tissue was performed using Illumina HumanHT-12 BeadChips. Protein and RNA binding studies, RNA-interference, a murine smoking model, and expression quantitative trait locus analyses were used to identify genes and proteins that may interact with three known COPD GWAS genes: IREB2, HHIP and FAM13A. Weighted Gene Co-Expression Network Analysis (WGCNA) was used to define co-expressed gene modules. Comparing 111 COPD cases and 40 control smokers, 214 genes were differentially expressed; none of these genes were at significant GWAS loci. However, the top differentially expressed gene was HMGB1, which interacts with AGER, a gene implicated through COPD GWAS. The genes differentially expressed in lung tissue showed strong enrichment for putative interactors of IREB2 and HHIP, with less support for FAM13A, based on the gene sets from the in vitro, in vivo, and in silico studies. In the WGCNA, the module most highly associated for COPD was enriched for B-cell pathways, which shared seventeen genes with the results of the Hhip+/- mouse smoking model. As in other common diseases, genes at COPD GWAS loci were not differentially expressed with COPD status; however, using a combination of network methods, experimental studies of interaction and careful phenotype definition, we found differential expression of putative interactors of these genes, and we replicated previous human and mouse microarray results involving B cell pathways.

Dataset Information

NHLBI TOPMed: Boston Early-Onset COPD Study in the TOPMed Program

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