TY - JOUR
T1 - Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
AU - The Qatar Genome Program Research (QGPR) Consortium
AU - Biobank and Sample Preparation
AU - Sequencing and Genotyping group
AU - Applied Bioinformatics Core
AU - Data Management and Computing Infrastructure group
AU - Consortium Lead Principal Investigators
AU - China Kadoorie Biobank Collaborative Group
AU - Shrine, Nick
AU - Izquierdo, Abril G.
AU - Chen, Jing
AU - Packer, Richard
AU - Hall, Robert J.
AU - Guyatt, Anna L.
AU - Batini, Chiara
AU - Thompson, Rebecca J.
AU - Pavuluri, Chandan
AU - Malik, Vidhi
AU - Hobbs, Brian D.
AU - Moll, Matthew
AU - Kim, Wonji
AU - Tal-Singer, Ruth
AU - Bakke, Per
AU - Fawcett, Katherine A.
AU - John, Catherine
AU - Coley, Kayesha
AU - Piga, Noemi Nicole
AU - Pozarickij, Alfred
AU - Lin, Kuang
AU - Millwood, Iona Y.
AU - Chen, Zhengming
AU - Li, Liming
AU - Wijnant, Sara R.A.
AU - Lahousse, Lies
AU - Brusselle, Guy
AU - Uitterlinden, Andre G.
AU - Manichaikul, Ani
AU - Oelsner, Elizabeth C.
AU - Rich, Stephen S.
AU - Barr, R. Graham
AU - Kerr, Shona M.
AU - Vitart, Veronique
AU - Brown, Michael R.
AU - Wielscher, Matthias
AU - Imboden, Medea
AU - Jeong, Ayoung
AU - Bartz, Traci M.
AU - Gharib, Sina A.
AU - Flexeder, Claudia
AU - Karrasch, Stefan
AU - Gieger, Christian
AU - Peters, Annette
AU - Stubbe, Beate
AU - Hu, Xiaowei
AU - Ortega, Victor E.
AU - Meyers, Deborah A.
AU - Albagha, Omar M.E.
AU - Puthen, Jithesh V.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/3
Y1 - 2023/3
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85150122193&partnerID=8YFLogxK
U2 - 10.1038/s41588-023-01314-0
DO - 10.1038/s41588-023-01314-0
M3 - Article
C2 - 36914875
AN - SCOPUS:85150122193
SN - 1061-4036
VL - 55
SP - 410
EP - 422
JO - Nature Genetics
JF - Nature Genetics
IS - 3
ER -