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Am J Respir Crit Care Med. 2016 Jun 15;193(12):1353-63. doi: 10.1164/rccm.201506-1223OC.

Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.

Author information

  • 11 Channing Division of Network Medicine.
  • 22 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
  • 33 Johns Hopkins Bloomberg School of Public Health, and.
  • 44 National Jewish Health, Denver, Colorado.
  • 55 Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland.
  • 66 Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington.
  • 77 Division of Pulmonary and Critical Care Medicine, and.
  • 88 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, Massachusetts.
  • 99 Department of Thoracic Medicine and Surgery, and.
  • 1010 Division of Thoracic Surgery, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
  • 1111 Division of Pulmonary and Critical Care Medicine Temple University School of Medicine, Philadelphia, Pennsylvania.



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.


To identify rare genetic determinants of severe COPD.


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. We tested 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.


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.


Rare deleterious coding variants may increase risk for COPD, but multiple genes likely contribute to COPD susceptibility.


chronic obstructive pulmonary disease; genetic association studies; segregation analysis

[Available on 2017-06-15]
[PubMed - in process]
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