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Exome Sequencing Analysis in Severe, Early-Onset Chronic Obstructive Pulmonary Disease
- Source :
- American Journal of Respiratory and Critical Care Medicine. 193:1353-1363
- Publication Year :
- 2016
- Publisher :
- American Thoracic Society, 2016.
-
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.
- Subjects :
- Adult
Male
0301 basic medicine
Pulmonary and Respiratory Medicine
Proband
Pulmonary disease
Pedigree chart
Critical Care and Intensive Care Medicine
Bioinformatics
Severity of Illness Index
Pulmonary Disease, Chronic Obstructive
03 medical and health sciences
0302 clinical medicine
Forced Expiratory Volume
alpha 1-Antitrypsin Deficiency
Humans
Medicine
Exome
Genetic Predisposition to Disease
Exome sequencing
Genetic association
Genetics
COPD
business.industry
Genetic heterogeneity
Editorials
High-Throughput Nucleotide Sequencing
Middle Aged
Heritability
medicine.disease
respiratory tract diseases
030104 developmental biology
030228 respiratory system
Original Article
Female
business
Boston
Genome-Wide Association Study
Subjects
Details
- ISSN :
- 15354970 and 1073449X
- Volume :
- 193
- Database :
- OpenAIRE
- Journal :
- American Journal of Respiratory and Critical Care Medicine
- Accession number :
- edsair.doi.dedup.....06f70fbfb09706365e73b1392d0d4052