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.

Dosage amplification dictates oncogenic regulation by theNKX2-1lineage factor in lung adenocarcinoma

“…In addition to lung adenocarcinoma, analysis of germline studies provides evidence for roles of the NKX2-1 SE in other diseases. The NKX2-1 SE harbors multiple SNP associations identified by genome-wide association studies (GWAS), including a thyroid cancer SNP in E10 (rs116909374 48 ) and a lung function FEV1/FVC SNP in E3-5 (rs10132289 49 ) ( Fig. S2e ).…”

“…In addition, our data suggests that focal enhancer amplification is a specifically critical oncogenic process in LUAD through targeting both the NKX2-1 and MYC 6 oncogenes, similar to the outsized role of regulatory translocations in hematopoietic malignancies 66 . The NKX2-1 SE also harbors risk variants for thyroid and lung cancer and developmental disorders 48,49 , including focal deletion events 51,52 , suggesting a broader role for the NKX2-1 SE in NKX2-1 expressing tissues and tumors.…”

“…(bottom) Minimal deletion region identified in a family for benign hereditary chorea (BHC) in (Invernizzi et al, 2018) 51 —multiple families with NKX2-1 proximal deletions not targeting the NKX2-1 gene have been documented 51 . (middle) A lung function (FEV1/FVC) associated allele rs10132289 identified (Shrine et al, 2023) 49 . Merged scATAC-seq accessibility profiles 47 for alveolar type 1 (AT1) and alveolar type 2 (AT2) distal lung cells as well as for thyroid follicular cells.…”

Genetic association of inflammatory marker GlycA with lung function and respiratory diseases

“…Six of above mentioned significant shared loci ( chr1p36 .11, chr3p21.31 , chr4p15.32 , chr6p22.1 , chr10q21.3 , and chr19q13.32 ) were possible candidate loci for lung function, asthma, or COPD (i.e., these loci were not previously reported to be associated with lung function, asthma, or COPD till we finished the analyses on February, 2023, see details in Supplementary Data 3 ). Interestingly, five of them ( chr1p36 .11, chr3p21.31 , chr4p15.32 , chr6p22.1 , and chr10q21.3 ) were also identified in the latest lung function GWAS 12 . Although FEV1/FVC ratio and PEF was only marginally significant related with GlycA, we also observed eleven and nine significant shared loci with GlycA, respectively (Supplementary Data 3 , P single trait < 1 × 10 −3 and P meta < 5 × 10 −8 ).…”

Associations of combined phenotypic ageing and genetic risk with incidence of chronic respiratory diseases in the UK Biobank: a prospective cohort study

“…In addition, we obtained the genome-wide association results of IPF GWAS in European descent from the International IPF Genetics Consortium [ 14 ]. Meanwhile, we also downloaded the genome-wide association results of COPD and asthma from the FinnGen GWAS results [ 26 ], as well as a database of lung function (including FEV 1 , FVC, FEV 1 /FVC and PEF) from a genome-wide meta-analysis [ 27 ]. Based on these genome-wide association results, PRS-CS, which employed a Bayesian regression framework with a continuous shrinkage prior to inferring the posterior mean effects of SNPs, was used to generate a global PRS with default settings [ 28 ].…”