Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
Authors: Shrine Nick , Izquierdo Abril G. , Chen Jing , Packer Richard , Hall Robert J. , Guyatt Anna L. , Batini Chiara , Thompson Rebecca J. , Pavuluri Chandan , Malik Vidhi , Hobbs Brian D. , Moll Matthew , Kim Wonji , Tal-Singer Ruth , Bakke Per , Fawcett Katherine A. , John Catherine , Coley Kayesha , Piga Noemi Nicole , Pozarickij Alfred , Lin Kuang , Millwood Iona Y. , Chen Zhengming , Li Liming ,   China Kadoorie Biobank Collaborative Group, Wijnant Sara R. A. , Lahousse Lies , Brusselle Guy , Uitterlinden Andre G. , Manichaikul Ani , Oelsner Elizabeth C. , Rich Stephen S. , Barr R. Graham , Kerr Shona M. , Vitart Veronique , Brown Michael R. , Wielscher Matthias , Imboden Medea , Jeong Ayoung , Bartz Traci M. , Gharib Sina A. , Flexeder Claudia , Karrasch Stefan , Gieger Christian , Peters Annette , Stubbe Beate , Hu Xiaowei , Ortega Victor E. , Meyers Deborah A. , Bleecker Eugene R. , Gabriel Stacey B. , Gupta Namrata , Smith Albert Vernon , Luan Jian’an , Zhao Jing-Hua , Hansen Ailin F. , Langhammer Arnulf , Willer Cristen , Bhatta Laxmi , Porteous David , Smith Blair H. , Campbell Archie , Sofer Tamar , Lee Jiwon , Daviglus Martha L. , Yu Bing , Lim Elise , Xu Hanfei , O’Connor George T. , Thareja Gaurav , Albagha Omar M. E. ,   The Qatar Genome Program Research (QGPR) Consortium, Ismail Said I. , Al-Muftah Wadha , Badji Radja , Mbarek Hamdi , Darwish Dima , Fadl Tasnim , Yasin Heba , Ennaifar Maryem , Abdellatif Rania , Alkuwari Fatima , Alvi Muhammad , Al-Sarraj Yasser , Saad Chadi , Althani Asmaa ,   Biobank and Sample Preparation, Fethnou Eleni , Qafoud Fatima , Alkhayat Eiman , Afifi Nahla ,   Sequencing and Genotyping group, Tomei Sara , Liu Wei , Lorenz Stephan ,   Applied Bioinformatics Core, Syed Najeeb , Almabrazi Hakeem , Vempalli Fazulur Rehaman , Temanni Ramzi ,   Data Management and Computing Infrastructure group, Saqri Tariq Abu , Khatib Mohammedhusen , Hamza Mehshad , Zaid Tariq Abu , El Khouly Ahmed , Pathare Tushar , Poolat Shafeeq , Al-Ali Rashid ,   Consortium Lead Principal Investigators, Al-Khodor Souhaila , Alshafai Mashael , Badii Ramin , Chouchane Lotfi , Estivill Xavier , Fakhro Khalid , Mokrab Younes , Puthen Jithesh V. , Tatari Zohreh , Suhre Karsten , Granell Raquel , Faquih Tariq O. , Hiemstra Pieter S. , Slats Annelies M. , Mullin Benjamin H. , Hui Jennie , James Alan , Beilby John , Patasova Karina , Hysi Pirro , Koskela Jukka T. , Wyss Annah B. , Jin Jianping , Sikdar Sinjini , Lee Mikyeong , May-Wilson Sebastian , Pirastu Nicola , Kentistou Katherine A. , Joshi Peter K. , Timmers Paul R. H. J. , Williams Alexander T. , Free Robert C. , Wang Xueyang , Morrison John L. , Gilliland Frank D. , Chen Zhanghua , Wang Carol A. , Foong Rachel E. , Harris Sarah E. , Taylor Adele , Redmond Paul , Cook James P. , Mahajan Anubha , Lind Lars , Palviainen Teemu , Lehtimäki Terho , Raitakari Olli T. , Kaprio Jaakko , Rantanen Taina , Pietiläinen Kirsi H. , Cox Simon R. , Pennell Craig E. , Hall Graham L. , Gauderman W. James , Brightling Chris , Wilson James F. , Vasankari Tuula , Laitinen Tarja , Salomaa Veikko , Mook-Kanamori Dennis O. , Timpson Nicholas J. , Zeggini Eleftheria , Dupuis Josée , Hayward Caroline , Brumpton Ben , Langenberg Claudia , Weiss Stefan , Homuth Georg , Schmidt Carsten Oliver , Probst-Hensch Nicole , Jarvelin Marjo-Riitta , Morrison Alanna C. , Polasek Ozren , Rudan Igor , Lee Joo-Hyeon , Sayers Ian , Rawlins Emma L. , Dudbridge Frank , Silverman Edwin K. , Strachan David P. , Walters Robin G. , Morris Andrew P. , London Stephanie J. , Cho Michael H. , Wain Louise V. , Hall Ian P. , Tobin Martin D. 
Published: March 2023

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 588,452 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.