Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk
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.
Author Correction: Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk: https://doi.org/10.1038/s41588-023-01531-7, published online 25 September 2023.
Other Information
Published in: Nature Genetics
License: https://creativecommons.org/licenses/by/4.0
See article on publisher's website: https://dx.doi.org/10.1038/s41588-023-01314-0
Additional institutions affiliated with: Qatar Precision Health Institute, Clinical Research Centre - Sidra Medicine
Funding
Department for Business, Energy and Industrial Strategy (MC_PC_19004), BREATHE - The Health Data Research Hub for Respiratory Health.
Wellcome Trust (204801/Z/16/Z), Institutional Strategic Support Fund.
British Heart Foundation (AA/18/3/34220), Accelerator Award (round 1).
Medical Research Council (MR/P00167X/1), Characterising the shared and disease-specific genetic determinants of asthma and COPD.
National Health and Medical Research Council (2003629), Analysis of the osteoclast methylome for characterisation of epigenetic mechanisms underlying metabolic bone disease.
Medical Research Council (MR/N011317/1), Discovery of genome-wide SNP associations for lung function.
Medical Research Council (G1000861), Defining the genetic contribution and functional role to altered lung function of genes identified by GWAS meta-analysis.
Medical Research Council (MR/S003762/1), Embracing multi-ethnicity in studying the genetics of smoking behaviour.
Medical Research Council (MC_UU_00007/10), Quantitative Traits in Health and Disease.
Medical Research Council (MR/P009581/1), Cellular and molecular control of human embryonic alveolar development: towards lung regeneration.
Wellcome Trust (202802/Z/16/Z), What lies behind the causal impact of body mass index (BMI) level and change on human health? Added value from complementary study design and deep metabolomic phenotyping.
Medical Research Council (MC_UU_00011/1), Mendelian randomization to hypothesis-free causal inference.
History
Language
- English
Publisher
Springer NaturePublication Year
- 2023
License statement
This Item is licensed under the Creative Commons Attribution 4.0 International License.Institution affiliated with
- Hamad Bin Khalifa University
- College of Health and Life Sciences - HBKU
- Weill Cornell Medicine - Qatar
- Qatar Genome Program (2015-2024)
- Qatar Biobank (2012-2024)
- Sidra Medicine
- Qatar University
- Qatar University Health - QU
- College of Health Sciences - QU HEALTH
- Hamad Medical Corporation