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

TitleExome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease.
Publication TypeJournal Article
Year of Publication2016
AuthorsQiao, D, Lange, C, Beaty, TH, Crapo, JD, Barnes, KC, Bamshad, M, Hersh, CP, Morrow, J, Pinto-Plata, VM, Marchetti, N, Bueno, R, Celli, BR, Criner, GJ, Silverman, EK, Cho, MH
Corporate AuthorsLung GO, NHLBI Exome Sequencing Project, COPDGene Investigators
JournalAm J Respir Crit Care Med
Volume193
Issue12
Pagination1353-63
Date Published2016 Jun 15
ISSN1535-4970
Abstract

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. 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.

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.

DOI10.1164/rccm.201506-1223OC
Alternate JournalAm. J. Respir. Crit. Care Med.
PubMed ID26736064
PubMed Central IDPMC4910887
Grant ListR01 HL113264 / HL / NHLBI NIH HHS / United States
R01 HL089897 / HL / NHLBI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States
P01 HL083069 / HL / NHLBI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
K08 HL097029 / HL / NHLBI NIH HHS / United States
R01 HL075478 / HL / NHLBI NIH HHS / United States
R01 HL089856 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
P01 HL105339 / HL / NHLBI NIH HHS / United States
K01 HL129039 / HL / NHLBI NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
R01 HL084323 / HL / NHLBI NIH HHS / United States