Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
Nick Shrine, Abril G. Izquierdo, Jing Chen, Richard Packer, Robert J. Hall, Anna L. Guyatt, Chiara Batini, Rebecca Thompson, Chandan Pavuluri, Vidhi Malik, Brian D. Hobbs, Matthew Moll, Wonji Kim, Ruth Tal‐Singer, Per Bakke, Katherine A. Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Alfred Pozarickij, Kuang Lin, Iona Y. Millwood, Zhengming Chen, Liming Li, China Kadoorie Biobank Collaborative Group, Sara Wijnant, Lies Lahousse, Guy Brusselle, André G. Uitterlinden, Ani Manichaikul, Elizabeth C. Oelsner, Stephen S. Rich, R. Graham Barr, Shona M. Kerr, Véronique 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 Gabriel, Namrata Gupta, Albert V. Smith, Jian’an Luan, Jinghua Zhao, Ailin Falkmo Hansen, Arnulf Langhammer, Cristen J. Willer, Laxmi Bhatta, David J. Porteous, Blair H. Smith, Archie Campbell, Tamar Sofer, Jiwon Lee, Martha L. Daviglus, Bing Yu, Elise Lim, Hanfei Xu, George O'connor, Gaurav Thareja, Omar Albagha, Said I. Ismail, Wadha Al‐Muftah, Radja Badji, Hamdi Mbarek, Dima Darwish, Tasnim Fadl, Heba Yasin, Maryem Ennaifar, Rania G. Abdel‐latif, Fatima Alkuwari, Muhammad Arshad Alvi, Yasser Al‐Sarraj, Chadi Saad, Asmaa Althani, Biobank and Sample Preparation, Eleni Fethnou, Fatima Qafoud, Eiman Alkhayat, Nahla Afifi, Sequencing and Genotyping group, Sara Tomei, Wei Liu, Stephan Lorenz, Applied Bioinformatics Core, Najeeb Syed, Hakeem Almabrazi, Fazulur Rehaman Vempalli, Ramzi Temanni, Data Management and Computing Infrastructure group
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.