Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
Creators: name: Shrine, Nick
name: Izquierdo, Abril G.
name: Chen, Jing
name: Packer, Richard
name: Hall, Robert J.
name: Guyatt, Anna L.
name: Batini, Chiara
name: Thompson, Rebecca J.
name: Pavuluri, Chandan
name: Malik, Vidhi
name: Hobbs, Brian D.
name: Moll, Matthew
name: Kim, Wonji
name: Tal-Singer, Ruth
name: Bakke, Per
name: Fawcett, Katherine A.
name: John, Catherine
name: Coley, Kayesha
name: Piga, Noemi Nicole
name: Pozarickij, Alfred
name: Lin, Kuang
name: Millwood, Iona Y.
name: Chen, Zhengming
name: Li, Liming
name: Wijnant, Sara R. A.
name: Lahousse, Lies
name: Brusselle, Guy
name: Uitterlinden, Andre G.
name: Manichaikul, Ani
name: Oelsner, Elizabeth C.
name: Rich, Stephen S.
name: Barr, R. Graham
name: Kerr, Shona M.
name: Vitart, Veronique
name: Brown, Michael R.
name: Wielscher, Matthias
name: Imboden, Medea
name: Jeong, Ayoung
name: Bartz, Traci M.
name: Gharib, Sina A.
name: Flexeder, Claudia
name: Karrasch, Stefan
name: Gieger, Christian
name: Peters, Annette
name: Stubbe, Beate
name: Hu, Xiaowei
name: Ortega, Victor E.
name: Meyers, Deborah A.
name: Bleecker, Eugene R.
name: Gabriel, Stacey B.
name: Gupta, Namrata
name: Smith, Albert Vernon
name: Luan, Jian’an
name: Zhao, Jing-Hua
name: Hansen, Ailin F.
name: Langhammer, Arnulf
name: Willer, Cristen
name: Bhatta, Laxmi
name: Porteous, David
name: Smith, Blair H.
name: Campbell, Archie
name: Sofer, Tamar
name: Lee, Jiwon
name: Daviglus, Martha L.
name: Yu, Bing
name: Lim, Elise
name: Xu, Hanfei
name: O’Connor, George T.
name: Thareja, Gaurav
name: Albagha, Omar M. E.
name: Suhre, Karsten
name: Granell, Raquel
name: Faquih, Tariq O.
name: Hiemstra, Pieter S.
name: Slats, Annelies M.
name: Mullin, Benjamin H.
name: Hui, Jennie
name: James, Alan
name: Beilby, John
name: Patasova, Karina
name: Hysi, Pirro
name: Koskela, Jukka T.
name: Wyss, Annah B.
name: Jin, Jianping
name: Sikdar, Sinjini
name: Lee, Mikyeong
name: May-Wilson, Sebastian
name: Pirastu, Nicola
name: Kentistou, Katherine A.
name: Joshi, Peter K.
name: Timmers, Paul R. H. J.
name: Williams, Alexander T.
name: Free, Robert C.
name: Wang, Xueyang
name: Morrison, John L.
name: Gilliland, Frank D.
name: Chen, Zhanghua
name: Wang, Carol A.
name: Foong, Rachel E.
name: Harris, Sarah E.
name: Taylor, Adele
name: Redmond, Paul
name: Cook, James P.
name: Mahajan, Anubha
name: Lind, Lars
name: Palviainen, Teemu
name: Lehtimäki, Terho
name: Raitakari, Olli T.
name: Kaprio, Jaakko
name: Rantanen, Taina
name: Pietiläinen, Kirsi H.
name: Cox, Simon R.
name: Pennell, Craig E.
name: Hall, Graham L.
name: Gauderman, W. James
name: Brightling, Chris
name: Wilson, James F.
name: Vasankari, Tuula
name: Laitinen, Tarja
name: Salomaa, Veikko
name: Mook-Kanamori, Dennis O.
name: Timpson, Nicholas J.
name: Zeggini, Eleftheria
name: Dupuis, Josée
name: Hayward, Caroline
name: Brumpton, Ben
name: Langenberg, Claudia
name: Weiss, Stefan
name: Homuth, Georg
name: Schmidt, Carsten Oliver
name: Probst-Hensch, Nicole
name: Jarvelin, Marjo-Riitta
name: Morrison, Alanna C.
name: Polasek, Ozren
name: Rudan, Igor
name: Lee, Joo-Hyeon
name: Sayers, Ian
name: Rawlins, Emma L.
name: Dudbridge, Frank
name: Silverman, Edwin K.
name: Strachan, David P.
name: Walters, Robin G.
name: Morris, Andrew P.
name: London, Stephanie J.
name: Cho, Michael H.
name: Wain, Louise V.
name: Hall, Ian P.
name: Tobin, Martin D.
Publisher: name: Apollo - University of Cambridge Repository
Year: 2023
Subjects: Article
/631/208/205/2138
/692/699/1785
/45/43
article

description: Funder: British Lung Foundation (BLF); doi: https://doi.org/10.13039/501100000351
description: Funder: DH | National Institute for Health Research (NIHR); doi: https://doi.org/10.13039/501100000272
description: 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.