Large-scale Multiancestry GWAS Study Identifies Genetic Signals Linked With COPD

A large lung function genomics study sought to uncover new genetic signals for chronic obstructive pulmonary disease (COPD) and lung function.

Up until now, there has been a lack of ancestral diversity in genome-wide association studies (GWAS) of lung function. The results of this multiancestry genome-wide study, using 49 diverse global cohorts, the largest to date in COPD, were published in Nature Genetics.

The study included a total of 580,869 individuals of African (n = 8590), American/Hispanic (n = 14,668), East Asian (n = 85,279), South Asian (n = 4270), and European (n = 468,062) ancestry.

Researchers analyzed forced expiratory vital capacity per 1 second (FEV₁), forced vital capacity (FVC), and forced expiratory volume per 1 second over forced vital capacity (FEV₁/FVC). Height was also factored into the analysis, as height is a determinant of lung growth.

From the meta-analysis, 1020 signals of 559 genes for lung function were identified after excluding for signals associated with smoking behaviors and after combining co-localized signals across traits. These genetic signals also met 2 or more criteria of the systemic variant-to-gene mapping framework.

The signals identified were then enriched in 29 pathways of functionally active regions in alveolar type 1 cells, fibroblasts, myofibroblasts, bronchial epithelial cells, and adult and fetal lung.

After mapping, 438 (43%) signals had a single putative causal variant. Of the 960 sentinel genes, 109 signals showed heterogeneity attributable to ancestry (P <.05), which was more than the researchers expected. Five of these signals that showed a strong heterogeneity were rs9393688, rs28574670 (LTBP4), rs7183859 (THSD4), rs59985551 (EFEMP1), and rs78101726 (MECOM).

“We highlight new putative causal variants, genes, proteins and pathways, including those targeted by existing drugs,” wrote the researchers.. “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.”

The researchers believe that these findings could potentially aid in the implementation of targeted therapies for people with COPD, and that these results exemplify possible outcomes of intervention.

“In summary, our multi-ancestry study highlights new putative causal variants, genes and pathways, some of which are targeted by existing drug compounds,” wrote the researchers. “These findings bring us closer to understanding mechanisms underlying lung function and COPD and will inform functional genomics experiments to confirm mechanisms and consequently guide the development of therapies for impaired lung function and COPD.”

Reference

Shrine N, Izquierdo AG, Chen J, et al. Multi-ancestry genome-wide association analyses improve resolution of genes and pathways influencing lung function and chronic obstructive pulmonary disease risk. Nature Genetics. 2023;55(3):410-422. doi:10.1038/s41588-023-01314-0