Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects

Authors

Robert Busch, Brigham and Women's HospitalFollow
Brian D. Hobbs, Brigham and Women's Hospital
Jin Zhou, University of Arizona
Peter J. Castaldi, Brigham and Women's Hospital
Michael J. McGeachie, Brigham and Women's Hospital
Megan E. Hardin, Brigham and Women's Hospital
Iwona Hawrylkiewicz, National Tuberculosis and Lung Disease Research Institute
Pawel Sliwinski, National Tuberculosis and Lung Disease Research Institute
Jae-Joon Yim, Seoul National University
Woo Jin Kim, Kangwon National University
Deog K. Kim, Seoul National University
Alvar Agusti, University of Barcelona
Barry J. Make, National Jewish Health
James D. Crapo, National Jewish Health
Peter M. Calverley, University of Liverpool
Claudio F. Donner, Mondo Medico di I.F.I.M. srl
David A. Lomas, University College London
Emiel F. Wouters, University Hospital Maastricht
Jorgen Vestbo, University of Machester
Ruth Tal-Singer, GlaxoSmithKline Research and Development
Per Bakke, University of Bergen
Amund Gulsvik, University of Bergen
Agusto A. Litonjua, Brigham and Women's Hospital
David Sparrow, Brigham and Women's Hospital and the Veterans Administration Medical Center
Peter D. Pare, University of British Columbia
Robert D. Levy, University of British Columbia
Stephen I. Rennard, UNMCFollow
Terri H. Beaty, Johns Hopkins University
John Hokanson, University of Colorado
Edwin K. Silverman, Brigham and Women's Hospital
Michael H. Cho, Brigham and Women's Hospital

ORCID IDs

0000-0003-0820-7164

0000-0001-9564-0745

0000-0002-4907-1657

Date of this Version

2017

Document Type

Article

Citation

Am J Respir Cell Mol Biol Vol 57, Iss 1, pp 35–46, Jul 2017

Comments

Copyright © 2017 by the American Thoracic Society

This document is a U.S. government work and is not subject to copyright in the United States.

DOI: 10.1165/rcmb.2016-0331OC

Abstract

The heritability of chronic obstructive pulmonary disease (COPD) cannot be fully explained by recognized genetic risk factors identified as achieving genome-wide significance. In addition, the combined contribution of genetic variation to COPD risk has not been fully explored. We sought to determine: (1) whether studies of variants from previous studies of COPD or lung function in a larger sample could identify additional associated variants, particularly for severe COPD; and (2) the impact of genetic risk scores on COPD. We genotyped 3,346 single-nucleotide polymorphisms (SNPs) in 2,588 cases (1,803 severe COPD) and 1,782 control subjects from four cohorts, and performed association testing with COPD, combining these results with existing genotyping data from 6,633 cases (3,497 severe COPD) and 5,704 control subjects. In addition, we developed genetic risk scores from SNPs associated with lung function and COPD and tested their discriminatory power for COPD-related measures. We identified significant associations between SNPs near PPIC (P = 1.28 X 10^-8) and PPP4R4/SERPINA1 (P = 1.0131028) and severe COPD; the latter association may be driven by recognized variants in SERPINA1. Genetic risk scores based on SNPs previously associated with COPD and lung function had a modest ability to discriminate COPD (area under the curve, ~0.6), and accounted for a mean 0.9–1.9% lower forced expiratory volume in 1 second percent predicted for each additional risk allele. In a large genetic association analysis, we identified associations with severe COPD near PPIC and SERPINA1. A risk score based on combining genetic variants had modest, but significant, effects on risk of COPD and lung function.