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COPD Genome-Wide Association Study Reveals Numerous Risk Variants

NEW YORK (GenomeWeb) – A pair of studies in Nature Genetics has linked new variants to risk of chronic obstructive pulmonary disease.

COPD is the third leading cause of death around the world, according to the World Health Organization, and the 2016 Global Burden of Disease study linked it to 2.9 million deaths that year. While smoking is a significant risk factor for COPD, other environmental exposures and genetics are also thought to influence disease risk.

The two research teams used data from the UK Biobank, which they combined with data from either the International COPD Genetics Consortium or the SpiroMeta Consortium to uncover hundreds of loci linked to COPD risk and lung function. The studies implicated genes and pathways in COPD risk, including the development of cilia and the lungs themselves.

"The global burden of COPD is increasing," Brigham and Women's Hospital's Michael Cho, the senior author of one of the studies, and his colleagues wrote. "Our work found a substantial number of new loci for COPD and used multiple lines of supportive evidence to identify potential genes and pathways for both existing and new loci."

In one paper, researchers led by the University of Leicester's Louise Wain conducted genome-wide association analyses of lung function in 321,047 individuals from the UK Biobank and 79,055 individuals from the SpiroMeta Consortium, all of European ancestry. They identified 279 signals associated with lung function, 139 of which were novel.

By identifying deleterious variants and variants linked to differences in gene expression or protein levels, the researchers homed in on 107 putative causal genes.

This set of genes was enriched for involvement in elastic fiber and extracellular matrix organization pathways as well as gene sets linked to cytoskeleton and ciliogenesis processes, including genes like KIAA0753, CDK2, and CEP72. Alterations to KIAA0753, the researchers noted, are associated with the ciliopathies Joubert syndrome and orofaciodigital syndrome. This finding suggested to the researchers that the reduced airway cilia motility that occurs in COPD could be a driver, rather than a consequence, of disease.

These variants also appear to influence lung function in non-European populations, the researchers reported. Wain and her colleagues tested a genetic risk score they developed based on their findings on other cohorts of European ancestry as well as an African-American cohort. They found similar effect sizes within the European cohort but a slightly smaller effect size within the African-American cohort.

A PheWas additionally noted connections between the 279 signals they identified and asthma.

Meanwhile, Cho and his colleagues performed their own GWAS of 35,735 cases and 222,076 controls that drew upon UK Biobank and International COPD Genetics Consortium cohorts. Through this analysis they linked 82 loci to COPD, 35 of which were novel loci. They tested those new loci within the SpiroMeta cohort, replicating 13 of them.

Through approximate conditional and joint analyses, they identified 82 secondary signals at 50 loci, 20 signals of which reached genome-wide significance, and zeroed in on 156 genes that were also implicated by gene expression, chromatin interaction, or other data. A number of these genes overlapped with those implicated in conditions like pulmonary fibrosis and asthma.

Through a gene-set enrichment analysis using the DEPICT tool, the researchers found these genes were overrepresented among lung alveolus development and lung morphogenesis pathways as well as extracellular matrix-related pathways.

This, the researchers said, suggests early-life events might influence later COPD risk, as they also noted an enrichment of epigenomic mark heritability in fetal lungs. Follow-up work is needed to determine whether high-risk individuals can be identified early on or treatment targets for those individuals, Cho and his colleagues added.

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