Whole exome sequencing analysis in severe chronic obstructive pulmonary disease

Abstract

Chronic obstructive pulmonary disease (COPD), one of the leading causes of death worldwide, is substantially influenced by genetic factors. Alpha-1 antitrypsin deficiency demonstrates that rare coding variants of large effect can influence COPD susceptibility. To identify additional rare coding variants in patients with severe COPD, we conducted whole exome sequencing analysis in 2543 subjects from two family-based studies (Boston Early-Onset COPD Study and International COPD Genetics Network) and one case-control study (COPDGene). Applying a gene-based segregation test in the family-based data, we identified significant segregation of rare loss of function variants in TBC1D10A and RFPL1 (P-value < 2x10-6), but were unable to find similar variants in the case-control study. In single-variant, gene-based and pathway association analyses, we were unable to find significant findings that replicated or were significant in meta-analysis. However, we found that the top results in the two datasets were in proximity to each other in the protein-protein interaction network (P-value = 0.014), suggesting enrichment of these results for similar biological processes. A network of these association results and their neighbors was significantly enriched in the transforming growth factor beta-receptor binding and cilia-related pathways. Finally, in a more detailed examination of candidate genes, we identified individuals with putative high-risk variants, including patients harboring homozygous mutations in genes associated with cutis laxa and Niemann-Pick Disease Type C. Our results likely reflect heterogeneity of genetic risk for COPD along with limitations of statistical power and functional annotation, and highlight the potential of network analysis to gain insight into genetic association studies.

Whole genome sequence analysis of pulmonary function and COPD in 19,996 multi-ethnic participants

“…(2) Mendelian candidate genes: The Bonferroni-corrected significance threshold was derived as P < 0.05/25 genes = 2.0 × 10 −3 to account for examination of 25 candidate Mendelian genes, selected for their relevance to COPD and emphysema, cutis laxa and the telomerase pathway (listed in Supplementary Table 3) 64,65 .…”

Genomic Predictors of Asthma Phenotypes and Treatment Response

“…More specifically, only a few asthma genetics studies have used NGS technologies (242, 243, 246) and large consortia studies are underway (247, 248). Because of its prohibitive costs for large population studies, several strategies have been proposed, such as sequencing the subjects from the extremes of the phenotype distribution (245, 246, 249) or the families where multiple individuals affected (250). The combination of NGS with conventional GWAS approaches has been suggested as another promising strategy (251).…”

Reliability of genomic variants across different next-generation sequencing platforms and bioinformatic processing pipelines

“…Another potential drawback of our study is that the used sequencing platforms have a legacy status and that the bulk of new data generated today stems from different platforms. Nevertheless, there is still a considerable number of recently published studies, which make use of older sequencing data from a wide variety of sources [24][25][26] and we believe this will continue to be the case. Common incentives for reanalyzing genomic cohorts include re-mapping reads to a new reference genome version [27], periodic reanalysis of disease cohorts to diagnose more patients [28] or large meta-GWAS [29], aiming to achieve statistically signi cant results by increasing sample sizes.…”