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Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk

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journal contribution
posted on 2023-11-15, 17:12 authored by Nicholas Shrine, Abril Izquierdo, Jing Chen, Richard Packer, Anna Guyatt, Chiara Batini, Katherine Fawcett, Catherine John, Kayesha Coley, Noemi Nicole Piga, Robert Free, Alexander Williams, Xueyang Wang, Chris Brightling, Frank Dudbridge, Louise Wain, Martin Tobin

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.


Institutional Strategic Support Fund

Wellcome Trust

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Accelerator Award (round 1)

British Heart Foundation

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NIH K08 HL136928, U01 HL089856, R01 HL155749, and a Research Grant from the Alpha-1 Foundation. B. Hobbs also receives grant support from Bayer – B.H.

Characterising the shared and disease-specific genetic determinants of asthma and COPD

Medical Research Council

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National Health and Medical Research Council (NHMRC) Ideas Grant 2003629 and Department of Health Western Australia Merit Award 1186046

BBSRC CASE studentship with GSK

GSK/British Lung Foundation Chair in Respiratory Research

Large-scale genomic epidemiology approaches to study the natural history of lung function and COPD

Wellcome Trust

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Wellcome Trust Discovery Award (WT225221/Z/22/Z)

MRC (MR/N011317/1)

MRC (G1000861

Wellcome Trust (WT098017 & WT064890)

Embracing multi-ethnicity in studying the genetics of smoking behaviour

Medical Research Council

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MRC Human Genetics Unit programme grant ‘Quantitative traits in health and disease’ (U. MC_UU_00007/10)

Academy of Finland (#336823) and Sigrid Juselius Foundation

Cellular and molecular control of human embryonic alveolar development: towards lung regeneration

Medical Research Council

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Author affiliation

Department of Population Health Sciences, University of Leicester


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Nature Genetics






Nature Research



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