Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

Shrine, N. and Izquierdo, A. G. and Chen, J. and Packer, R. and Hall, R. J. and Guyatt, A. L. and Batini, C. and Thompson, R. J. and Pavuluri, C. and Malik, V. and Hobbs, B. D. and Moll, M. and Kim, W. and Tal-Singer, R. and Bakke, P. and Fawcett, K. A. and John, C. and Coley, K. and Piga, N. N. and Pozarickij, A. and Lin, K. and Millwood, I. Y. and Chen, Z. and Li, L. and Wijnant, S. R. A. and Lahousse, L. and Brusselle, G. and Uitterlinden, A. G. and Manichaikul, A. and Oelsner, E. C. and Rich, S. S. and Barr, R. G. and Kerr, S. M. and Vitart, V. and Brown, M. R. and Wielscher, M. and Imboden, M. and Jeong, A. and Bartz, T. M. and Gharib, S. A. and Flexeder, C. and Karrasch, S. and Gieger, C. and Peters, A. and Stubbe, B. and Hu, X. and Ortega, V. E. and Meyers, D. A. and Bleecker, E. R. and Gabriel, S. B. and Gupta, N. and Smith, A. V. and Luan, J. and Zhao, J. H. and Hansen, A. F. and Langhammer, A. and Willer, C. and Bhatta, L. and Porteous, D. and Smith, B. H. and Campbell, A. and Sofer, T. and Lee, J. and Daviglus, M. L. and Yu, B. and Lim, E. and Xu, H. and O'Connor, G. T. and Thareja, G. and Albagha, O. M. E. and Qatar Genome Program Research Consortium, and Suhre, K. and Granell, R. and Faquih, T. O. and Hiemstra, P. S. and Slats, A. M. and Mullin, B. H. and Hui, J. and James, A. and Beilby, J. and Patasova, K. and Hysi, P. and Koskela, J. T. and Wyss, A. B. and Jin, J. and Sikdar, S. and Lee, M. and May-Wilson, S. and Pirastu, N. and Kentistou, K. A. and Joshi, P. K. and Timmers, Prhj and Williams, A. T. and Free, R. C. and Wang, X. and Morrison, J. L. and Gilliland, F. D. and Chen, Z. and Wang, C. A. and Foong, R. E. and Harris, S. E. and Taylor, A. and Redmond, P. and Cook, J. P. and Mahajan, A. and Lind, L. and Palviainen, T. and Lehtimäki, T. and Raitakari, O. T. and Kaprio, J. and Rantanen, T. and Pietiläinen, K. H. and Cox, S. R. and Pennell, C. E. and Hall, G. L. and Gauderman, W. J. and Brightling, C. and Wilson, J. F. and Vasankari, T. and Laitinen, T. and Salomaa, V. and Mook-Kanamori, D. O. and Timpson, N. J. and Zeggini, E. and Dupuis, J. and Hayward, C. and Brumpton, B. and Langenberg, C. and Weiss, S. and Homuth, G. and Schmidt, C. O. and Probst-Hensch, N. and Jarvelin, M. R. and Morrison, A. C. and Polasek, O. and Rudan, I. and Lee, J. H. and Sayers, I. and Rawlins, E. L. and Dudbridge, F. and Silverman, E. K. and Strachan, D. P. and Walters, R. G. and Morris, A. P. and London, S. J. and Cho, M. H. and Wain, L. V. and Hall, I. P. and Tobin, M. D.. (2023) Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nat Genet, 55 (3). pp. 410-422.

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Official URL: https://edoc.unibas.ch/94574/

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Lung-function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry genome-wide association meta-analysis of lung function to date, comprising 580,869 participants, we identified 1,020 independent association signals implicating 559 genes supported by >/=2 criteria from a systematic variant-to-gene mapping framework. These genes were enriched in 29 pathways. Individual variants showed heterogeneity across ancestries, age and smoking groups, and collectively as a genetic risk score showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies for selected associated variants as well as trait and pathway-specific genetic risk scores to infer possible consequences of intervening in pathways underlying lung function. We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs. These findings bring us closer to understanding the mechanisms underlying lung function and COPD, and should inform functional genomics experiments and potentially future COPD therapies.
Faculties and Departments:09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH)
09 Associated Institutions > Swiss Tropical and Public Health Institute (Swiss TPH) > Department of Epidemiology and Public Health (EPH) > Chronic Disease Epidemiology > Exposome Science (Probst-Hensch)
03 Faculty of Medicine > Departement Public Health > Sozial- und Präventivmedizin > Exposome Science (Probst-Hensch)
UniBasel Contributors:Imboden, Medea and Probst-Hensch, Nicole and Jeong, Ayoung
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1546-1718 (Electronic)1061-4036 (Print)1061-4036 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:09 May 2023 07:31
Deposited On:09 May 2023 07:31

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