Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk.
Shrine N., Izquierdo AG., Chen J., Packer R., Hall RJ., Guyatt AL., Batini C., Thompson RJ., Pavuluri C., Malik V., Hobbs BD., Moll M., Kim W., Tal-Singer R., Bakke P., Fawcett KA., John C., Coley K., Piga NN., Pozarickij A., Lin K., Millwood IY., Chen Z., Li L., China Kadoorie Biobank Collaborative Group None., Wijnant SRA., Lahousse L., Brusselle G., Uitterlinden AG., Manichaikul A., Oelsner EC., Rich SS., Barr RG., Kerr SM., Vitart V., Brown MR., Wielscher M., Imboden M., Jeong A., Bartz TM., Gharib SA., Flexeder C., Karrasch S., Gieger C., Peters A., Stubbe B., Hu X., Ortega VE., Meyers DA., Bleecker ER., Gabriel SB., Gupta N., Smith AV., Luan J., Zhao J-H., Hansen AF., Langhammer A., Willer C., Bhatta L., Porteous D., Smith BH., Campbell A., Sofer T., Lee J., Daviglus ML., Yu B., Lim E., Xu H., O'Connor GT., Thareja G., Albagha OME., Qatar Genome Program Research (QGPR) Consortium None., Suhre K., Granell R., Faquih TO., Hiemstra PS., Slats AM., Mullin BH., Hui J., James A., Beilby J., Patasova K., Hysi P., Koskela JT., Wyss AB., Jin J., Sikdar S., Lee M., May-Wilson S., Pirastu N., Kentistou KA., Joshi PK., Timmers PRHJ., Williams AT., Free RC., Wang X., Morrison JL., Gilliland FD., Chen Z., Wang CA., Foong RE., Harris SE., Taylor A., Redmond P., Cook JP., Mahajan A., Lind L., Palviainen T., Lehtimäki T., Raitakari OT., Kaprio J., Rantanen T., Pietiläinen KH., Cox SR., Pennell CE., Hall GL., Gauderman WJ., Brightling C., Wilson JF., Vasankari T., Laitinen T., Salomaa V., Mook-Kanamori DO., Timpson NJ., Zeggini E., Dupuis J., Hayward C., Brumpton B., Langenberg C., Weiss S., Homuth G., Schmidt CO., Probst-Hensch N., Jarvelin M-R., Morrison AC., Polasek O., Rudan I., Lee J-H., Sayers I., Rawlins EL., Dudbridge F., Silverman EK., Strachan DP., Walters RG., Morris AP., London SJ., Cho MH., Wain LV., Hall IP., Tobin MD.
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.