Multi-ancestry genome-wide association study improves resolution of genes, pathways and pleiotropy for lung function and chronic obstructive pulmonary disease

Abstract

Lung function impairment underlies chronic obstructive pulmonary disease (COPD) and predicts mortality. In the largest multi-ancestry GWAS meta-analysis of lung function to date, comprising 580,869 participants, 1020 independent association signals identified 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 (GRS) showed strong association with COPD across ancestry groups. We undertook phenome-wide association studies (PheWAS) for selected associated variants, and trait and pathway-specific GRS 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.

Leveraging deep-learning on raw spirograms to improve genetic understanding and risk scoring of COPD despite noisy labels

“…Finally, we note that recently, a larger GWAS of lung function has been published; some of our novel findings are confirmed by examination in a larger sample size. For example, rs72703234 (near DMRT 2) did not meet replication criteria in Shrine et al [14], but was reported in 2022 [47].…”

Genome-wide association study of thyroid-stimulating hormone highlights new genes, pathways and associations with thyroid disease susceptibility and age-of-onset

“…We show contrasting patterns of phenotype association -for example highly specific associations for hypothyroidism (cAMP signalling) versus associations also with body composition, renal function and lipid traits (platelet activation pathways). As individuals may have high GRS for one or more pathways and low GRS for other pathways (17), individuals' pathway GRS profiles may relate to patterns of comorbidities, and could have implications for treatment choices in thyroid diseases.…”

ERS International Congress 2022: highlights from the Epidemiology and Environment Assembly

“…First, Nick Shrine presented a multi-ancestry genome-wide association study (GWAS) of lung function, based on data arising from 49 different cohorts (n=580,869) including individuals with European, African, American, East, and South Asian ancestries [32]. By exploring multiple ancestries, Shrine et al identified over 1,000 independent signals for lung function, and proposed a novel multi-ancestry genetic risk score that is more predictive of lung function in diverse populations, compared to previous European ancestry genetic risk scores [33]. Second, Mohammad Talaei Pashiri presented an investigation of 55 lung development genes that aimed to explore shared development pathways explaining the association between lower lung function in adulthood and cardiovascular health, in the UK Biobank [34].…”

“…By exploring multiple ancestries, S hrine et al . [ 33 ] identified >1000 independent signals for lung function and proposed a novel multi-ancestry genetic risk score that is more predictive of lung function in diverse populations compared to previous European ancestry genetic risk scores. Second, T alaei P ashiri et al [ 34 ] presented an investigation of 55 lung development genes that aimed to explore shared development pathways explaining the association between lower lung function in adulthood and cardiovascular health, in the UK Biobank.…”