. 2020 Jul;8(7):696-708.

doi: 10.1016/S2213-2600(20)30101-6.

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Matthew Moll¹, Phuwanat Sakornsakolpat², Nick Shrine³, Brian D Hobbs¹, Dawn L DeMeo¹, Catherine John³, Anna L Guyatt³, Michael J McGeachie⁴, Sina A Gharib⁵, Ma'en Obeidat⁶, Lies Lahousse⁷, Sara R A Wijnant⁸, Guy Brusselle⁹, Deborah A Meyers¹⁰, Eugene R Bleecker¹⁰, Xingnan Li¹⁰, Ruth Tal-Singer¹¹, Ani Manichaikul¹², Stephen S Rich¹², Sungho Won¹³, Woo Jin Kim¹⁴, Ah Ra Do¹⁵, George R Washko¹⁶, R Graham Barr¹⁷, Bruce M Psaty¹⁸, Traci M Bartz¹⁹, Nadia N Hansel²⁰, Kathleen Barnes²¹, John E Hokanson²², James D Crapo²³, David Lynch²⁴, Per Bakke²⁵, Amund Gulsvik²⁶, Ian P Hall²⁷, Louise Wain²⁸; International COPD Genetics Consortium; SpiroMeta Consortium; Scott T Weiss⁴, Edwin K Silverman²⁹, Frank Dudbridge³, Martin D Tobin³⁰, Michael H Cho³¹

Collaborators, Affiliations

Collaborators

María Soler Artigas, Victoria E Jackson, David P Strachan, Jennie Hui, Alan L James, Shona M Kerr, Ozren Polasek, Veronique Vitart, Jonathan Marten, Igor Rudan, Mika Kähönen, Ida Surakka, Christian Gieger, Stefan Karrasch, Rajesh Rawal, Holger Schulz, Ian J Deary, Sarah E Harris, Stefan Enroth, Ulf Gyllensten, Medea Imboden, Nicole M Probst-Hensch, Terho Lehtimäki, Olli T Raitakari, Claudia Langenberg, Jian'an Luan, Nick Wareham, Jing Hua Zhao, Caroline Hayward, Alison Murray, David J Porteous, Blair H Smith, Marjo-Riitta Jarvelin, Matthias Wielscher, Peter K Joshi, Katherine A Kentistou, Paul Rhj Timmers, James F Wilson, James P Cook, Lars Lind, Anubha Mahajan, Andrew P Morris, Ralf Ewert, Georg Homuth, Beate Stubbe, Stefan Weiss, Eleftheria Zeggini

Affiliations

¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
³ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Computational Medicine Core, Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
⁷ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
⁸ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
⁹ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁰ Department of Medicine, University of Arizona, Tucson, AZ, USA.
¹¹ GlaxoSmithKline Research and Development, Collegeville, PA, USA.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹³ Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, South Korea; Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, South Korea; Institute of Health and Environment, Seoul National University, Seoul, South Korea.
¹⁴ Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea.
¹⁵ Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, South Korea.
¹⁶ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, NY, USA.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
²¹ Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²² School of Public Health, University of Colorado, Denver.
²³ Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.
²⁴ Department of Radiology, National Jewish Health, Denver, CO, USA.
²⁵ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁶ Division of Respiratory Medicine, Queen's Medical Centre, Nottingham, UK.
²⁷ National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁸ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
³⁰ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK. Electronic address: martin.tobin@leicester.ac.uk.
³¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: remhc@channing.harvard.edu.

PMID: 32649918
PMCID: PMC7429152
DOI: 10.1016/S2213-2600(20)30101-6

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Matthew Moll et al. Lancet Respir Med. 2020 Jul.

. 2020 Jul;8(7):696-708.

doi: 10.1016/S2213-2600(20)30101-6.

Authors

Collaborators

María Soler Artigas, Victoria E Jackson, David P Strachan, Jennie Hui, Alan L James, Shona M Kerr, Ozren Polasek, Veronique Vitart, Jonathan Marten, Igor Rudan, Mika Kähönen, Ida Surakka, Christian Gieger, Stefan Karrasch, Rajesh Rawal, Holger Schulz, Ian J Deary, Sarah E Harris, Stefan Enroth, Ulf Gyllensten, Medea Imboden, Nicole M Probst-Hensch, Terho Lehtimäki, Olli T Raitakari, Claudia Langenberg, Jian'an Luan, Nick Wareham, Jing Hua Zhao, Caroline Hayward, Alison Murray, David J Porteous, Blair H Smith, Marjo-Riitta Jarvelin, Matthias Wielscher, Peter K Joshi, Katherine A Kentistou, Paul Rhj Timmers, James F Wilson, James P Cook, Lars Lind, Anubha Mahajan, Andrew P Morris, Ralf Ewert, Georg Homuth, Beate Stubbe, Stefan Weiss, Eleftheria Zeggini

Affiliations

¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Department of Medicine, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand.
³ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK.
⁴ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA.
⁵ Computational Medicine Core, Center for Lung Biology, Department of Medicine, University of Washington, Seattle, WA, USA; Division of Pulmonary, Critical Care, and Sleep Medicine, Department of Medicine, University of Washington, Seattle, WA, USA.
⁶ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; University of British Columbia Center for Heart Lung Innovation, St Paul's Hospital, Vancouver, BC, Canada.
⁷ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium.
⁸ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Bioanalysis, Faculty of Pharmaceutical Sciences, Ghent University, Ghent, Belgium; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
⁹ Department of Epidemiology, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Respiratory Medicine, Erasmus Medical Centre, Rotterdam, Netherlands; Department of Respiratory Medicine, Ghent University Hospital, Ghent, Belgium.
¹⁰ Department of Medicine, University of Arizona, Tucson, AZ, USA.
¹¹ GlaxoSmithKline Research and Development, Collegeville, PA, USA.
¹² Center for Public Health Genomics, University of Virginia, Charlottesville, VA, USA; Department of Public Health Sciences, University of Virginia, Charlottesville, VA, USA.
¹³ Department of Public Health Sciences, Graduate School of Public Health, Seoul National University, Seoul, South Korea; Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, South Korea; Institute of Health and Environment, Seoul National University, Seoul, South Korea.
¹⁴ Department of Internal Medicine, Kangwon National University, Chuncheon, South Korea.
¹⁵ Interdisciplinary Program of Bioinformatics, College of National Sciences, Seoul National University, Seoul, South Korea.
¹⁶ Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA.
¹⁷ Department of Medicine and Department of Epidemiology, Columbia University Medical Center, New York, NY, USA.
¹⁸ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA; Kaiser Permanente Washington Health Research Institute, Seattle, WA.
¹⁹ Cardiovascular Health Research Unit, Department of Medicine, University of Washington, Seattle, WA, USA.
²⁰ School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
²¹ Colorado Center for Personalized Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
²² School of Public Health, University of Colorado, Denver.
²³ Division of Pulmonary, Critical Care, and Sleep Medicine, National Jewish Health, Denver, CO, USA.
²⁴ Department of Radiology, National Jewish Health, Denver, CO, USA.
²⁵ Department of Clinical Science, University of Bergen, Bergen, Norway.
²⁶ Division of Respiratory Medicine, Queen's Medical Centre, Nottingham, UK.
²⁷ National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁸ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK.
²⁹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA.
³⁰ Genetic Epidemiology Group, Department of Health Sciences, University of Leicester, Leicester, UK; National Institute for Health Research Leicester Respiratory Biomedical Research Centre, Glenfield Hospital, Leicester, UK. Electronic address: martin.tobin@leicester.ac.uk.
³¹ Channing Division of Network Medicine, Brigham and Women's Hospital, Boston, MA, USA; Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Boston, MA, USA. Electronic address: remhc@channing.harvard.edu.

PMID: 32649918
PMCID: PMC7429152
DOI: 10.1016/S2213-2600(20)30101-6

Erratum in

Correction to Lancet Respir Med 2020; 8: 696-708.
[No authors listed] [No authors listed] Lancet Respir Med. 2024 Nov;12(11):e70. doi: 10.1016/S2213-2600(24)00326-6. Lancet Respir Med. 2024. PMID: 39481921 Free PMC article. No abstract available.

Abstract

Background: Genetic factors influence chronic obstructive pulmonary disease (COPD) risk, but the individual variants that have been identified have small effects. We hypothesised that a polygenic risk score using additional variants would predict COPD and associated phenotypes.

Methods: We constructed a polygenic risk score using a genome-wide association study of lung function (FEV₁ and FEV₁/forced vital capacity [FVC]) from the UK Biobank and SpiroMeta. We tested this polygenic risk score in nine cohorts of multiple ethnicities for an association with moderate-to-severe COPD (defined as FEV₁/FVC <0·7 and FEV₁ <80% of predicted). Associations were tested using logistic regression models, adjusting for age, sex, height, smoking pack-years, and principal components of genetic ancestry. We assessed predictive performance of models by area under the curve. In a subset of studies, we also studied quantitative and qualitative CT imaging phenotypes that reflect parenchymal and airway pathology, and patterns of reduced lung growth.

Findings: The polygenic risk score was associated with COPD in European (odds ratio [OR] per SD 1·81 [95% CI 1·74-1·88] and non-European (1·42 [1·34-1·51]) populations. Compared with the first decile, the tenth decile of the polygenic risk score was associated with COPD, with an OR of 7·99 (6·56-9·72) in European ancestry and 4·83 (3·45-6·77) in non-European ancestry cohorts. The polygenic risk score was superior to previously described genetic risk scores and, when combined with clinical risk factors (ie, age, sex, and smoking pack-years), showed improved prediction for COPD compared with a model comprising clinical risk factors alone (AUC 0·80 [0·79-0·81] vs 0·76 [0·75-0·76]). The polygenic risk score was associated with CT imaging phenotypes, including wall area percent, quantitative and qualitative measures of emphysema, local histogram emphysema patterns, and destructive emphysema subtypes. The polygenic risk score was associated with a reduced lung growth pattern.

Interpretation: A risk score comprised of genetic variants can identify a small subset of individuals at markedly increased risk for moderate-to-severe COPD, emphysema subtypes associated with cigarette smoking, and patterns of reduced lung growth.

Funding: US National Institutes of Health, Wellcome Trust.

PubMed Disclaimer

Figures

**Figure 1**
Study design AUC=area under the curve. COPD=chronic obstructive pulmonary disease. FVC=forced vital capacity. GWAS=genome-wide association study. PRS=polygenic risk score.

**Figure 2**
Association of combined PRS with chronic obstructive pulmonary disease AA=African American participants. CHS=Cardiovascular Health Study. EA=European ancestry. NAS=Normative Aging Study. NHW=non-Hispanic white participants. OR=odds ratio. PRS=polygenic risk score. RS=Rotterdam Study.

**Figure 3**
Analysis of OR for COPD by PRS decile (A) ORs for COPD for those in each decile of the PRS in comparison with the first decile in European cohorts and non-European cohorts. Data are shown as ORs with 95% CIs. (B) A secondary meta-analysis comparing COPD risk for participants in the tenth decile with those in the middle tertile of the combined PRS. COPD=chronic obstructive pulmonary disease. AA=African American. NAS=Normative Aging Study. NHW=non-Hispanic white participants. OR=odds ratio. PRS=polygenic risk score.

**Figure 4**
AUC for predicting chronic obstructive pulmonary disease of models including PRS alone, clinical risk factors alone, or both PRS and clinical risk factors AUCs with 95% CIs are shown. Only European cohorts are included in this figure. Asterisks indicate the models including PRS and clinical risk factors for which the AUCs were significantly different from those with clinical risk factors alone (Bonferroni-corrected significance level of 0·005; appendix pp 14–15). Note that an AUC of 0·5 represents the effect assumed under the null model. AUC=area under the curve. EA=European ancestry. NAS=Normative Aging Study. NHW=non-Hispanic white participants. PRS=polygenic risk score.

See this image and copyright information in PMC

Comment in

Exacerbations in Chronic Obstructive Pulmonary Disease: Clinical, Genetic, and Mycobiome Risk Factors.
Matsumoto K, Read N, Philip KEJ, Allinson JP. Matsumoto K, et al. Am J Respir Crit Care Med. 2023 Aug 15;208(4):487-489. doi: 10.1164/rccm.202303-0581RR. Am J Respir Crit Care Med. 2023. PMID: 37104845 No abstract available.

References

1. Vogelmeier CF, Criner GJ, Martinez FJ. Global strategy for the diagnosis, management, and prevention of chronic obstructive lung disease 2017 report: GOLD executive summary. Am J Respir Crit Care Med. 2017;195:557–582. - PubMed
1. Fletcher C, Peto R, Tinker CSF. Oxford University Press; Oxford: 1976. The natural history of chronic bronchitis and emphysema: an eight-year study of early chronic obstructive lung disease in working men in London.
1. Rennard SI, Vestbo J. COPD: the dangerous underestimate of 15% Lancet. 2006;367:1216–1219. - PubMed
1. Wilk JB, Djousse L, Arnett DK. Evidence for major genes influencing pulmonary function in the NHLBI family heart study. Genet Epidemiol. 2000;19:81–94. - PubMed
1. Palmer LJ, Knuiman MW, Divitini ML. Familial aggregation and heritability of adult lung function: results from the Busselton Health Study. Eur Respir J. 2001;17:696–702. - PubMed

Publication types

Actions
Actions

MeSH terms

Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions
Actions

Grants and funding

LinkOut - more resources

Full Text Sources
Medical
- MedlinePlus Health Information

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Collaborators

Affiliations

Chronic obstructive pulmonary disease and related phenotypes: polygenic risk scores in population-based and case-control cohorts

Authors

Collaborators

Affiliations

Erratum in

Abstract

Figures

Comment in

References

Publication types

MeSH terms

Grants and funding

LinkOut - more resources

Full Text Sources

Medical