Journal article
Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects
American journal of respiratory cell and molecular biology, Vol.57(1), pp.35-46
07/2017
DOI: 10.1165/rcmb.2016-0331OC
PMCID: PMC5516277
PMID: 28170284
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 × 10
) and PPP4R4/SERPINA1 (P = 1.01 × 10
) 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.
Details
- Title: Subtitle
- Genetic Association and Risk Scores in a Chronic Obstructive Pulmonary Disease Meta-analysis of 16,707 Subjects
- Creators
- Robert Busch - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsBrian D Hobbs - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsJin Zhou - 2 University of Arizona, Tucson, ArizonaPeter J Castaldi - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsMichael J McGeachie - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsMegan E Hardin - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsIwona Hawrylkiewicz - 3 National Tuberculosis and Lung Disease Research Institute, Warsaw, PolandPawel Sliwinski - 3 National Tuberculosis and Lung Disease Research Institute, Warsaw, PolandJae-Joon Yim - 4 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Seoul National University College of Medicine, Seoul, KoreaWoo Jin Kim - 5 Kangwon National University, Chuncheon, KoreaDeog K Kim - 6 Seoul National University College of Medicine Boramae Medical Center, Seoul, KoreaAlvar Agusti - 7 Thorax Institute, Hospital Clinic, IDIBAPS, University of Barcelona, CIBERES, Barcelona, SpainBarry J Make - 8 National Jewish Health, Denver, ColoradoJames D Crapo - 8 National Jewish Health, Denver, ColoradoPeter M Calverley - 9 University of Liverpool, Liverpool, United KingdomClaudio F Donner - 10 Mondo Medico di I.F.I.M. srl, Multidisciplinary and Rehabilitation Outpatient Clinic, Borgomanero, Novara, ItalyDavid A Lomas - 11 University College London, London, United KingdomEmiel F Wouters - 12 University Hospital Maastricht, Maastricht, the NetherlandsJørgen Vestbo - 13 University of Manchester, Manchester, United KingdomRuth Tal-Singer - 14 GlaxoSmithKline Research and Development, King of Prussia, PennsylvaniaPer Bakke - 15 University of Bergen, Bergen, NorwayAmund Gulsvik - 15 University of Bergen, Bergen, NorwayAugusto A Litonjua - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsDavid Sparrow - 16 Brigham and Women's Hospital and the Veterans Administration Medical Center-Jamaica Plain, Jamaica Plain, MassachusettsPeter D Paré - 17 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, CanadaRobert D Levy - 17 Respiratory Division, Department of Medicine, University of British Columbia, Vancouver, British Columbia, CanadaStephen I Rennard - 18 University of Nebraska Medical Center, Omaha, NebraskaTerri H Beaty - 19 Department of Epidemiology, Bloomberg School of Public Health, the Johns Hopkins University, Baltimore, Maryland; andJohn Hokanson - 20 Department of Epidemiology, University of Colorado Anschutz Medical Campus, Aurora, ColoradoEdwin K Silverman - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsMichael H Cho - 1 Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MassachusettsNational Emphysema Treatment Trial GeneticsEvaluation of COPD Longitudinally to Identify Predictive Surrogate End-PointsInternational COPD Genetics NetworkCOPDGene Investigators
- Contributors
- Eric A Hoffman (Contributor) - University of Iowa, Radiology
- Resource Type
- Journal article
- Publication Details
- American journal of respiratory cell and molecular biology, Vol.57(1), pp.35-46
- DOI
- 10.1165/rcmb.2016-0331OC
- PMID
- 28170284
- PMCID
- PMC5516277
- NLM abbreviation
- Am J Respir Cell Mol Biol
- ISSN
- 1044-1549
- eISSN
- 1535-4989
- Publisher
- United States
- Grant note
- N01HR76107 / NHLBI NIH HHS MR/N024842/1 / Medical Research Council N01HR76102 / NHLBI NIH HHS R01 HL124233 / NHLBI NIH HHS N01HR76104 / NHLBI NIH HHS R01 HL113264 / NHLBI NIH HHS K01 DK106116 / NIDDK NIH HHS N01HR76110 / NHLBI NIH HHS N01 HR076115 / NHLBI NIH HHS U01 HL089856 / NHLBI NIH HHS N01HR76109 / NHLBI NIH HHS N01HR76113 / NHLBI NIH HHS N01HR76106 / NHLBI NIH HHS N01HR76119 / NHLBI NIH HHS N01HR76103 / NHLBI NIH HHS P30 ES005605 / NIEHS NIH HHS N01HR76111 / NHLBI NIH HHS T32 HL007427 / NHLBI NIH HHS U01 HL089897 / NHLBI NIH HHS R01 HL089856 / NHLBI NIH HHS P01 HL114501 / NHLBI NIH HHS N01HR76114 / NHLBI NIH HHS R25 ES011080 / NIEHS NIH HHS N01HR76116 / NHLBI NIH HHS R01 HL126596 / NHLBI NIH HHS N01HR76108 / NHLBI NIH HHS N01HR76105 / NHLBI NIH HHS N01HR76101 / NHLBI NIH HHS P01 HL105339 / NHLBI NIH HHS S10 OD018526 / NIH HHS N01HR76118 / NHLBI NIH HHS N01HR76112 / NHLBI NIH HHS R01 HL089897 / NHLBI NIH HHS
- Language
- English
- Date published
- 07/2017
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Radiology; Internal Medicine
- Record Identifier
- 9984051597502771
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