Abstract
Background: Chronic obstructive pulmonary disease (COPD) is caused by interactions between many factors across the life course, including genetics. A proportion of COPD may be due to reduced lung growth in childhood. We hypothesized that a polygenic risk score (PRS) for COPD is associated with lower lung function already in childhood and up to adulthood. Methods: A weighted PRS was calculated based on the 82 association signals (p ≤ 5 × 10−8) revealed by the largest GWAS of airflow limitation (defined as COPD) to date. This PRS was tested in association with lung function measures (FEV1, FVC, and FEV1/FVC) in subjects aged 4–50 years from 16 independent cohorts participating in the Chronic Airway Diseases Early Stratification (CADSET) Clinical Research Collaboration. Age-stratified meta-analyses were conducted combining the results from each cohort (n = 45,406). These findings were validated in subjects >50 years old. Findings: We found significant associations between the PRS for airflow limitation and: (1) lower pre-bronchodilator FEV1/FVC from school age (7–10 years; β: −0.13 z-scores per one PRS z-score increase [–0.15, −0.11], q-value = 7.04 × 10−53) to adulthood (41–50 years; β: −0.16 [–0.19, −0.13], q-value = 1.31 × 10−24); and (2) lower FEV1 (from school age: 7–10 years; β: −0.07 [–0.09, −0.05], q-value = 1.65 × 10−9, to adulthood: 41–50 years; β: −0.17 [–0.20, −0.13], q-value = 4.48 x 10−20). No effect modification by smoking, sex, or a diagnosis of asthma was observed. Interpretation: We provide evidence that a higher genetic risk for COPD is linked to lower lung function from childhood onwards. Funding: This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.
| Original language | English |
|---|---|
| Article number | 102731 |
| Journal | EClinicalMedicine |
| Volume | 75 |
| Early online date | 12 Aug 2024 |
| DOIs | |
| Publication status | Published - Sept 2024 |
Bibliographical note
Publisher Copyright:© 2024 The Author(s)
Funding
This study was funded by the program of Clinical Research Collaborations of the European Respiratory Society (ERS). The CADSET Clinical Research Collaboration and this study, in particular, have been financially supported by AstraZeneca UK, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi Genzyme. ISGlobal is supported by the grant CEX2018-000806-S funded by MCIN/AEI/ 10.13039/501100011033, and by the Generalitat de Catalunya through the CERCA Program. The IUF is funded by the federal and state governments - the Ministry of Culture and Science of North Rhine-Westphalia (MKW) and the Federal Ministry of Education and Research (BMBF). Analysis of Ashford, ALSPAC, IoWBC, and MAAS was supported by the UK Medical Research Council MR/S025340/1. The Isle of Wight Birth Cohort assessments were supported by the National Institutes of Health USA (Grant no. R01 HL082925, R01AI121226), Asthma UK (Grant no. 364) and the David Hide Asthma and Allergy Research Trust. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Raquel Granell will serve as guarantor for the contents of this paper. A comprehensive list of grant funding is available on the ALSPAC website ( http://www.bristol.ac.uk/alspac/external/documents/ grant-acknowledgements.pdf). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, MSc, for the creation and analysis of imputed data. The INMA cohort was funded by the Spanish Biomedical Research Center in Epidemiology and Public Health (CIBERESP) and by grants from the Instituto de Salud Carlos III (PI06/0867, PI09/00090, PI13/02187, PI18/01142, PI21/01491, CB06/02/0041, G03/176, PI041436, PI081151, PI041705, and PS09/00432, PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, and PI17/01225 and PI17/01935) cofunded by ERDF, \u201CA way to make Europe\u201D, the Basque Department of Health (Projects GV-SAN2005111093, GV-SAN2009111069, GV-SAN2013111089, GV-SAN2015111065, and GV-SAN2018111086, GV-SAN2019111085), the Provincial Government of Gipuzkoa (Projects DFG06/002, DFG08/001 and DFG15/221), annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia, Azpeitia, and Beasain), Fundaci\u00F3 La Marat\u00F3 de TV3 (090430), Generalitat de Catalunya-CIRIT (1999SGR 00241), Conselleria de Sanitat Generalitat Valenciana, and Fundaci\u00F3n Roger Torn\u00E9. ISGlobal acknowledges the support from the Spanish Ministry of Science and Innovation and the State Research Agency through the \u201CCentro de Excelencia Severo Ochoa 2019-2023\u201D Program (CEX2018-000806-S), and the support from the Generalitat de Catalunya through the CERCA Program. The Tr\u00F8ndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU)), Tr\u00F8ndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The PIAMA study was supported by The Netherlands Organization for Health Research and Development; The Netherlands Organization for Scientific Research; the Lung Foundation of the Netherlands (specifically grant AF 4.1.20.003); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. This study was supported by CADSET, a Clinical Research Collaboration of the European Respiratory Society.This study was funded by the program of Clinical Research Collaborations of the European Respiratory Society (ERS). The CADSET Clinical Research Collaboration and this study, in particular, have been financially supported by AstraZeneca UK, Chiesi Farmaceutici, GlaxoSmithKline, Menarini, and Sanofi Genzyme. ISGlobal is supported by the grant CEX2018-000806-S funded by MCIN/AEI/10.13039/501100011033, and by the Generalitat de Catalunya through the CERCA Program. The IUF is funded by the federal and state governments\u2013the Ministry of Culture and Science of North Rhine-Westphalia (MKW) and the Federal Ministry of Education and Research (BMBF). Analysis of Ashford, ALSPAC, IoWBC, and MAAS was supported by the UK Medical Research Council MR/S025340/1. The Isle of Wight Birth Cohort assessments were supported by the National Institutes of Health USA (Grant no. R01 HL082925, R01AI121226), Asthma UK (Grant no. 364) and the David Hide Asthma and Allergy Research Trust. The UK Medical Research Council and Wellcome (Grant ref: 217065/Z/19/Z) and the University of Bristol provide core support for ALSPAC. This publication is the work of the authors and Raquel Granell will serve as guarantor for the contents of this paper. A comprehensive list of grant funding is available on the ALSPAC website (http://www.bristol.ac.uk/alspac/external/documents/grant-acknowledgements.pdf). The Rotterdam Study is funded by Erasmus Medical Center and Erasmus University, Rotterdam, Netherlands Organization for the Health Research and Development (ZonMw), the Research Institute for Diseases in the Elderly (RIDE), the Ministry of Education, Culture, and Science, the Ministry for Health, Welfare and Sports, the European Commission (DG XII), and the Municipality of Rotterdam. The authors are grateful to the study participants, the staff from the Rotterdam Study, and the participating general practitioners and pharmacists. The generation and management of GWAS genotype data for the Rotterdam Study (RS I, RS II, RS III) was executed by the Human Genotyping Facility of the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands. The GWAS datasets are supported by the Netherlands Organisation of Scientific Research NWO Investments (nr. 175.010.2005.011, 911-03-012), the Genetic Laboratory of the Department of Internal Medicine, Erasmus MC, the Research Institute for Diseases in the Elderly (014-93-015; RIDE2), the Netherlands Genomics Initiative (NGI)/Netherlands Organisation for Scientific Research (NWO) Netherlands Consortium for Healthy Aging (NCHA), project nr. 050-060-810. We thank Pascal Arp, Mila Jhamai, Marijn Verkerk, Lizbeth Herrera and Marjolein Peters, MSc, and Carolina Medina-Gomez, MSc, for their help in creating the GWAS database, and Karol Estrada, PhD, Yurii Aulchenko, PhD, and Carolina Medina-Gomez, MSc, for the creation and analysis of imputed data. The INMA cohort was funded by the Spanish Biomedical Research Center in Epidemiology and Public Health (CIBERESP) and by grants from the Instituto de Salud Carlos III (PI06/0867, PI09/00090, PI13/02187, PI18/01142, PI21/01491, CB06/02/0041, G03/176, PI041436, PI081151, PI041705, and PS09/00432, PI03/1615, PI04/1509, PI04/1112, PI04/1931, PI05/1079, PI05/1052, PI06/1213, PI07/0314, PI09/02647, and PI17/01225 and PI17/01935) cofunded by ERDF, \u201CA way to make Europe\u201D, the Basque Department of Health (Projects GV-SAN2005111093, GV-SAN2009111069, GV-SAN2013111089, GV-SAN2015111065, and GV-SAN2018111086, GV-SAN2019111085), the Provincial Government of Gipuzkoa (Projects DFG06/002, DFG08/001 and DFG15/221), annual agreements with the municipalities of the study area (Zumarraga, Urretxu, Legazpi, Azkoitia, Azpeitia, and Beasain), Fundaci\u00F3 La Marat\u00F3 de TV3 (090430), Generalitat de Catalunya-CIRIT (1999SGR 00241), Conselleria de Sanitat Generalitat Valenciana, and Fundaci\u00F3n Roger Torn\u00E9. ISGlobal acknowledges the support from the Spanish Ministry of Science and Innovation and the State Research Agency through the \u201CCentro de Excelencia Severo Ochoa 2019\u20132023\u201D Program (CEX2018-000806-S), and the support from the Generalitat de Catalunya through the CERCA Program. The Tr\u00F8ndelag Health Study (HUNT) is a collaboration between HUNT Research Centre (Faculty of Medicine and Health Sciences at Norwegian University of Science and Technology (NTNU)), Tr\u00F8ndelag County Council, Central Norway Regional Health Authority, and the Norwegian Institute of Public Health. The PIAMA study was supported by The Netherlands Organisation for Health Research and Development; The Netherlands Organisation for Scientific Research; the Lung Foundation Netherlands (specifically grant AF 4.1.20.003); The Netherlands Ministry of Spatial Planning, Housing, and the Environment; and The Netherlands Ministry of Health, Welfare, and Sport. The BAMSE study was supported by grants from The Swedish Research Council, The Swedish Heart-Lung Foundation, and Region Stockholm (ALF).
| Funders | Funder number |
|---|---|
| Spanish Biomedical Research Center in Epidemiology and Public Health | |
| Helse Midt-Norge | |
| HUNT Research Centre | |
| Centro de Excelencia Severo Ochoa 2019-2023 | |
| CIBERESP | |
| Erasmus Universiteit Rotterdam | |
| Nederlandse Organisatie voor Wetenschappelijk Onderzoek | |
| Ministerio de Ciencia e Innovación | |
| Generalitat de Catalunya | |
| Norges Teknisk-Naturvitenskapelige Universitet | |
| European Respiratory Society | |
| Netherlands Ministry of Spatial Planning | |
| Research Institute for Diseases in the Elderly | |
| Lung Foundation Netherlands | |
| AstraZeneca UK | |
| State Research Agency | |
| Bundesministerium für Bildung und Forschung | |
| European Commission | |
| Ministerie van Volksgezondheid, Welzijn en Sport | |
| Netherlands Ministry of Health, Welfare, and Sport | |
| Fakultet for medisin og helsevitenskap, Norges Teknisk-Naturvitenskapelige Universitet | |
| Agencia Estatal de Investigación | |
| Trøndelag County Council | |
| Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen | |
| Fundación Roger Torné | |
| ZonMw | |
| CADSET | |
| Chiesi Farmaceutici | |
| Norwegian Institute of Public Health | |
| RIDE2 | |
| University of Bristol | |
| European Regional Development Fund | |
| Conselleria de Sanitat Universal i Salut Pública | |
| Hjärt-Lungfonden | |
| Ministerie van onderwijs, cultuur en wetenschap | |
| Vetenskapsrådet | |
| David Hide Asthma and Allergy Research Trust | |
| Sociale en Geesteswetenschappen, NWO | |
| Wellcome Trust | 217065/Z/19/Z |
| GlaxoSmithKline | MCIN/AEI/10.13039/501100011033, CEX2018-000806-S |
| Generalitat de Catalunya-CIRIT | 1999SGR 00241 |
| Netherlands Consortium for Healthy Aging | 050-060-810 |
| National Institutes of Health | R01AI121226, R01 HL082925 |
| Asthma and Lung UK | 364 |
| Lung Foundation of the Netherlands | AF 4.1.20.003 |
| Provincial Government of Gipuzkoa | DFG08/001, DFG15/221, DFG06/002 |
| Medical Research Council | MR/S025340/1 |
| Instituto de Salud Carlos III | PI041436, PI18/01142, PI13/02187, PI081151, PI03/1615, PI06/1213, PI21/01491, PI09/02647, PI041705, CB06/02/0041, G03/176, PI05/1052, PI06/0867, PI17/01225, PI05/1079, PI04/1509, PI04/1931, PI09/00090, PI17/01935, PS09/00432, PI07/0314, PI04/1112 |
| Basque Department of Health | GV-SAN2015111065, GV-SAN2009111069, GV-SAN2018111086, GV-SAN2013111089, GV-SAN2019111085, GV-SAN2005111093 |
| Netherlands Organisation of Scientific Research NWO | 175.010.2005.011, 911-03-012 |
| Erasmus Medisch Centrum | 014-93-015 |
| Fundació la Marató de TV3 | 090430 |
Keywords
- Chronic obstructive pulmonary disease
- Genetics
- Lung function
- Polygenic risk score