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Am J Respir Cell Mol Biol. 2018 Nov;59(5):614-622. doi: 10.1165/rcmb.2018-0088OC.

Whole-Genome Sequencing in Severe Chronic Obstructive Pulmonary Disease.

Author information

1 Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts.
2 Working Group of Genomic Mathematics, University of Bonn, Bonn, Germany.
3 Department of Biostatistics, Harvard School of Public Health, Boston, Massachusetts.
4 Division of Pulmonary, Allergy and Critical Care Medicine, University of Alabama at Birmingham, Birmingham, Alabama.
5 Center for Public Health Genomics, University of Virginia, Charlottesville, Virginia.
6 Department of Medicine, College of Physicians and Surgeons and.
7 Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, New York.
8 Division of Pulmonary Critical Care and Sleep Medicine, College of Medicine, University of Florida, Gainesville, Florida.
9 Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland; and.
10 National Jewish Health, Denver, Colorado.


Genome-wide association studies have identified common variants associated with chronic obstructive pulmonary disease (COPD). Whole-genome sequencing (WGS) offers comprehensive coverage of the entire genome, as compared with genotyping arrays or exome sequencing. We hypothesized that WGS in subjects with severe COPD and smoking control subjects with normal pulmonary function would allow us to identify novel genetic determinants of COPD. We sequenced 821 patients with severe COPD and 973 control subjects from the COPDGene and Boston Early-Onset COPD studies, including both non-Hispanic white and African American individuals. We performed single-variant and grouped-variant analyses, and in addition, we assessed the overlap of variants between sequencing- and array-based imputation. Our most significantly associated variant was in a known region near HHIP (combined P = 1.6 × 10-9); additional variants approaching genome-wide significance included previously described regions in CHRNA5, TNS1, and SERPINA6/SERPINA1 (the latter in African American individuals). None of our associations were clearly driven by rare variants, and we found minimal evidence of replication of genes identified by previously reported smaller sequencing studies. With WGS, we identified more than 20 million new variants, not seen with imputation, including more than 10,000 of potential importance in previously identified COPD genome-wide association study regions. WGS in severe COPD identifies a large number of potentially important functional variants, with the strongest associations being in known COPD risk loci, including HHIP and SERPINA1. Larger sample sizes will be needed to identify associated variants in novel regions of the genome.


association studies; chronic obstructive pulmonary disease; whole-genome sequencing

[Available on 2019-11-01]

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