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; Lung GO; NHLBI Exome Sequencing Project; COPDGene Investigators

doi:10.1164/rccm.201506-1223OC

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

Journal article

Open access

Peer reviewed

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, …

American journal of respiratory and critical care medicine, Vol.193(12), pp.1353-1363

06/15/2016

DOI: 10.1164/rccm.201506-1223OC

PMCID: PMC4910887

PMID: 26736064

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Abstract

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.

Severity of Illness Index

alpha 1-Antitrypsin Deficiency - genetics

Exome - genetics

Genetic Predisposition to Disease - genetics

Humans

Middle Aged

Adult

Female

Male

Genome-Wide Association Study - methods

Boston

Pulmonary Disease, Chronic Obstructive - genetics

Details

Title: Subtitle: Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease
Creators: Dandi Qiao - 1 Channing Division of Network Medicine
Christoph Lange - 2 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts
Terri H Beaty - 3 Johns Hopkins Bloomberg School of Public Health, and
James D Crapo - 4 National Jewish Health, Denver, Colorado
Kathleen C Barnes - 5 Division of Allergy and Clinical Immunology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland
Michael Bamshad - 6 Division of Genetic Medicine, Department of Pediatrics, University of Washington and Seattle Children's Hospital, Seattle, Washington
Craig P Hersh - 7 Division of Pulmonary and Critical Care Medicine, and
Jarrett Morrow - 1 Channing Division of Network Medicine
Victor M Pinto-Plata - 8 Department of Critical Care Medicine and Pulmonary Disease, Baystate Medical Center, Springfield, Massachusetts
Nathaniel Marchetti - 9 Department of Thoracic Medicine and Surgery, and
Raphael Bueno - 10 Division of Thoracic Surgery, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts
Bartolome R Celli - 7 Division of Pulmonary and Critical Care Medicine, and
Gerald J Criner - 11 Division of Pulmonary and Critical Care Medicine Temple University School of Medicine, Philadelphia, Pennsylvania
Edwin K Silverman - 7 Division of Pulmonary and Critical Care Medicine, and
Michael H Cho - 7 Division of Pulmonary and Critical Care Medicine, and
Lung GO
NHLBI Exome Sequencing Project
COPDGene Investigators
Contributors: Eric A Hoffman (Contributor) - University of Iowa, Radiology
Resource Type: Journal article
Publication Details: American journal of respiratory and critical care medicine, Vol.193(12), pp.1353-1363
DOI: 10.1164/rccm.201506-1223OC
PMID: 26736064
PMCID: PMC4910887
NLM abbreviation: Am J Respir Crit Care Med
ISSN: 1073-449X
eISSN: 1535-4970
Publisher: United States
Grant note: RC2 HL103010 / NHLBI NIH HHS U54 HG006493 / NHGRI NIH HHS P01 HL083069 / NHLBI NIH HHS K01 HL129039 / NHLBI NIH HHS RC2 HL102924 / NHLBI NIH HHS R01 HL084323 / NHLBI NIH HHS R01 HL089856 / NHLBI NIH HHS RC2 HL102923 / NHLBI NIH HHS RC2 HL102926 / NHLBI NIH HHS R01 HL113264 / NHLBI NIH HHS R01 HL075478 / NHLBI NIH HHS UM1 HG006493 / NHGRI NIH HHS P01 HL105339 / NHLBI NIH HHS K08 HL097029 / NHLBI NIH HHS R01 HL089897 / NHLBI NIH HHS RC2 HL102925 / NHLBI NIH HHS
Language: English
Date published: 06/15/2016
Academic Unit: Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
Record Identifier: 9984051868502771

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