@article{e61b632360f24d7ea12016175bbe3a79,
title = "Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk",
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.",
keywords = "Humans, Lung, Genome-Wide Association Study, Genetic Predisposition to Disease/genetics, Pulmonary Disease, Chronic Obstructive/genetics, Smoking/adverse effects, Polymorphism, Single Nucleotide/genetics",
author = "Nick Shrine and Izquierdo, \{Abril G.\} and Jing Chen and Richard Packer and Hall, \{Robert J.\} and Guyatt, \{Anna L\} and Chiara Batini and Thompson, \{Rebecca J.\} and Chandan Pavuluri and Vidhi Malik and Hobbs, \{Brian D\} and Matthew Moll and Wonji Kim and Ruth Tal-Singer and Per Bakke and Fawcett, \{Katherine A\} and Catherine John and Kayesha Coley and Piga, \{Noemi Nicole\} and Alfred Pozarickij and Kuang Lin and Millwood, \{Iona Y\} and Zhengming Chen and Liming Li and Wijnant, \{Sara R. A.\} and Lies Lahousse and Guy Brusselle and Uitterlinden, \{Andre G.\} and Ani Manichaikul and Oelsner, \{Elizabeth C.\} and Rich, \{Stephen S\} and Barr, \{R Graham\} and Kerr, \{Shona M\} and Veronique Vitart and Brown, \{Michael R\} and Matthias Wielscher and Medea Imboden and Ayoung Jeong and Bartz, \{Traci M\} and Gharib, \{Sina A\} and Claudia Flexeder and Stefan Karrasch and Christian Gieger and Annette Peters and Beate Stubbe and Xiaowei Hu and Ortega, \{Victor E\} and Meyers, \{Deborah A\} and Bleecker, \{Eugene R\} and Smith, \{Blair H\}",
note = "Funding Information: This research has been conducted using the UK Biobank Resource under Application Number 648. We used the ALICE High Performance Computing Facility at the University of Leicester. This study was supported by BREATHE{\textendash}The Health Data Research Hub for Respiratory Health (grant no. MC\_PC\_19004). This study was partially supported by the NIHR Leicester Biomedical Research Centre and the NIHR Nottingham Biomedical Research Centre; views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health. The funders had no role in the design of the study. This research was funded in part by the Wellcome Trust. For the purpose of open access, the authors have applied a CC BY public copyright license to any author accepted paper version arising from this submission. Cohort- and study-group-specific acknowledgements and funding information are in the Supplementary Note. This study was also supported by specific personal funding from the following: Wellcome Trust Institutional Strategic Support Fund (grant no. 204801/Z/16/Z) and BHF Accelerator Award AA/18/3/34220 to A.L.G.; NIH K08 HL136928, U01 HL089856, R01 HL155749 and a Research Grant from the Alpha-1 Foundation to B.D.H., B.D.H. also receives grant support from Bayer; Medical Research Council Clinical Research Training Fellowship (grant no. MR/P00167X/1) to C.J.; National Health and Medical Research Council (NHMRC) Ideas grant no. 2003629 and Department of Health Western Australia Merit Award 1186046 to B.H.M.; BBSRC CASE studentship with GSK to A.T.W.; GSK/British Lung Foundation Chair in Respiratory Research (L.V.W.); Wellcome Trust Investigator Award (WT202849/Z/16/Z) and Wellcome Trust Discovery Award (WT225221/Z/22/Z) to M.D.T.; MRC grant no. MR/N011317/1 to M.D.T. and L.V.W.; NIHR Senior Investigator Award to M.D.T. and I.P.H.; MRC grant no. G1000861 to I.S.; Wellcome Trust grant nos. WT098017 and WT064890 to A.P.M.; UKRI Innovation Fellowship at Health Data Research UK grant no. MR/S003762/1 to C.B.; MRC Human Genetics Unit program grant {\textquoteleft}Quantitative traits in health and disease{\textquoteright} (grant no. U. MC\_UU\_00007/10) to C.H., V.V. and S.M.K.; Academy of Finland (grant no. 336823) and Sigrid Juselius Foundation to J.K.; and MRC grant no. MR/P009581/1 to E.L.R.N.J.T. is a Wellcome Trust Investigator (202802/Z/16/Z), is the PI of the Avon Longitudinal Study of Parents and Children (MRC \& WT 217065/Z/19/Z), is supported by the University of Bristol NIHR Biomedical Research Centre (BRC-1215-2001) and the MRC Integrative Epidemiology Unit (MC\_UU\_00011/1) and works within the CRUK Integrative Cancer Epidemiology Programme (C18281/A29019). Copyright: {\textcopyright} The Author(s) 2023",
year = "2023",
month = mar,
doi = "10.1038/s41588-023-01314-0",
language = "English",
volume = "55",
pages = "410--422",
journal = "Nature Genetics",
issn = "1061-4036",
publisher = "Nature Research",
number = "3",
}