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

China Kadoorie Biobank Collaborative Group, Qatar Genome Program Research (QGPR) Consortium, Nick Shrine, Abril G. Izquierdo, Jing Chen, Richard Packer, Robert J. Hall, Anna L. Guyatt, Chiara Batini, Rebecca J. Thompson, Chandan Pavuluri, Vidhi Malik, Brian D. Hobbs, Matthew Moll, Wonji Kim, Ruth Tal-Singer, Per Bakke, Katherine A. Fawcett, Catherine John, Kayesha ColeyNoemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y. Millwood, Zhengming Chen, Liming Li, Sara R.A. Wijnant, Lies Lahousse, Guy Brusselle, Andre G. Uitterlinden, Ani Manichaikul, Elizabeth C. Oelsner, Stephen S. Rich, R. Graham Barr, Shona M. Kerr, Veronique Vitart, Michael R. Brown, Matthias Wielscher, Medea Imboden, Ayoung Jeong, Traci M. Bartz, Sina A. Gharib, Claudia Flexeder, Stefan Karrasch, Christian Gieger, Annette Peters, Beate Stubbe, Xiaowei Hu, Victor E. Ortega, Deborah A. Meyers, Eugene R. Bleecker, Stacey B. Gabriel, Namrata Gupta, Albert Vernon Smith, Jian'an Luan, Jing Hua Zhao, Ailin F. Hansen, Arnulf Langhammer, Cristen Willer, Laxmi Bhatta, David Porteous, Blair H. Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L. Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George T. O'Connor, Gaurav Thareja, Omar M.E. Albagha, Karsten Suhre, Raquel Granell, Tariq O. Faquih, Pieter S. Hiemstra, Annelies M. Slats, Benjamin H. Mullin, Jennie Hui, Alan James, John Beilby, Karina Patasova, Pirro Hysi, Jukka T. Koskela, Annah B. Wyss, Jianping Jin, Sinjini Sikdar, Mikyeong Lee, Sebastian May-Wilson, Nicola Pirastu, Katherine A. Kentistou, Peter K. Joshi, Paul R.H.J. Timmers, Alexander T. Williams, Robert C. Free, Xueyang Wang, John L. Morrison, Frank D. Gilliland, Zhanghua Chen, Carol A. Wang, Rachel E. Foong, Sarah E. Harris, Adele Taylor, Paul Redmond, James P. Cook, Anubha Mahajan, Lars Lind, Teemu Palviainen, Terho Lehtimäki, Olli T. Raitakari, Jaakko Kaprio, Taina Rantanen, Kirsi H. Pietiläinen, Simon R. Cox, Craig E. Pennell, Graham L. Hall, W. James Gauderman, Chris Brightling, James F. Wilson, Tuula Vasankari, Tarja Laitinen, Veikko Salomaa, Dennis O. Mook-Kanamori, Nicholas J. Timpson, Eleftheria Zeggini, Josée Dupuis, Caroline Hayward, Ben Brumpton, Claudia Langenberg, Stefan Weiss, Georg Homuth, Carsten Oliver Schmidt, Nicole Probst-Hensch, Marjo Riitta Jarvelin, Alanna C. Morrison, Ozren Polasek, Igor Rudan, Joo Hyeon Lee, Ian Sayers, Emma L. Rawlins, Frank Dudbridge, Edwin K. Silverman, David P. Strachan, Robin G. Walters, Andrew P. Morris, Stephanie J. London, Michael H. Cho, Louise V. Wain, Ian P. Hall, Martin D. Tobin

Research output: Contribution to journalArticlepeer-review

22 Citations (Web of Science)

Abstract

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.

Original languageEnglish
Pages (from-to)410-422
Number of pages13
JournalNature Genetics
Volume55
Issue number3
DOIs
Publication statusPublished - Mar 2023

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