Exome sequencing analysis in severe, early-onset chronic obstructive pulmonary disease

Dandi Qiao, Christoph Lange, Terri H. Beaty, James D. Crapo, Kathleen C. Barnes, Michael Bamshad, Craig P. Hersh, Jarrett Morrow, Victor M. Pinto-Plata, Nathaniel Marchetti, Raphael Bueno, Bartolome R. Celli, Gerald J. Criner, Edwin K. Silverman, Michael H. Cho

Research output: Contribution to journalArticlepeer-review

25 Scopus citations


Rationale: Genomic regions identified by genome-wide association studies explain only a small fraction of heritability for chronic obstructive pulmonary disease (COPD). Alpha-1 antitrypsin deficiency shows that rare coding variants of large effect also influence COPD susceptibility. We hypothesized that exome sequencing in families identified through a proband with severe, early-onset COPD would identify additional rare genetic determinants of large effect. Objectives: To identify rare genetic determinants of severe COPD. Methods: We applied filtering approaches to identify potential causal variants for COPD in whole exomes from 347 subjects in 49 extended pedigrees from the Boston Early-Onset COPD Study. We assessed the power of this approach under different levels of genetic heterogeneity using simulations.Wetested genes identified in these families using gene-based association tests in exomes of 204 cases with severe COPD and 195 resistant smokers from the COPDGene study. In addition, we examined previously described loci associated with COPD using these datasets. Measurements and Main Results: We identified 69 genes with predicted deleterious nonsynonymous, stop, or splice variants that segregated with severe COPD in at least two pedigrees. Four genes (DNAH8, ALCAM, RARS, and GBF1) also demonstrated an increase in rare nonsynonymous, stop, and/or splice mutations in cases compared with resistant smokers from the COPDGene study; however, these results were not statistically significant. We demonstrate the limitations of the power of this approach under genetic heterogeneity through simulation. Conclusions: Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.

Original languageEnglish (US)
Pages (from-to)1353-1363
Number of pages11
JournalAmerican journal of respiratory and critical care medicine
Issue number12
StatePublished - Jun 15 2016


  • Chronic Obstructive Pulmonary Disease
  • Genetic Association Studies
  • Segregation Analysis

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine


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