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Lung Function GWAS Meta-Analysis Yields Insights Into Healthy, Diseased States

NEW YORK – An international team led by investigators in the UK has identified hundreds of genes with apparent ties to lung function within and across ancestry groups, providing a look at the pathways behind lung health and disease.

"Ultimately genetic studies of this kind can improve [lung disease] prediction, prevention, diagnosis, and/or treatment," co-senior and co-corresponding author Martin Tobin, a population health sciences researcher at the University of Leicester and Glenfield Hospital's Leicester National Institute for Health and Care Research, said in an email.

As they reported in Nature Genetics on Monday, Tobin and his colleagues did a genome-wide association study meta-analysis that involved nearly 581,000 individuals from dozens of European, Africa, East Asian, South Asian, or American/Hispanic ancestry cohorts enrolled in past studies, searching for genetic variants and loci with ties to four lung function measurements such as forced expiratory volume per second and peak expiratory flow rate.

In the process, the team tracked down lung function-related associations involving 1,028 distinct variants, including 1,020 smoking behavior-independent associations involving known risk SNPs and another 713 previously unappreciated variants.

The investigators tapped into the smoking-independent risk variant set to focus in on 559 candidate causal genes from 29 pathways, while establishing genetic risk scores (GRS) linked to lung function, chronic obstructive pulmonary disease (COPD), and biological pathway features found in a subsequent phenome-wide association analysis.

"We used a method using eight different criteria to relate these associated genomic regions to causal genes," Tobin explained. "Building on these mapped genes we constructed pathway-specific genetic scores which could be powerful tools in developing and targeting drug treatments effectively."

"Development of new treatments can be a lengthy process," he added, "but the evidence and tools we provide could help to shorten this process for COPD and potentially other respiratory disease."

The precise genetic risk variants implicated in the lung function traits varied between individuals from one ancestry group to the next, and shifted depending on individuals' smoking history, the researchers reported. Even so, they were able to establish a GRS that coincided with COPD risk across ancestry groups.

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

By incorporating drug-gene database interactions, the investigators estimated that dozens of the candidate causal genes may be amenable to targeting by 292 existing drugs. With a PheWAS approach, meanwhile, they took a closer look at the biological traits and pathways coinciding with a subset of genes impacted by variants from lung function- or pathway-specific GRS, pointing to the consequences of potential treatments or interventions targeting the same genes or pathways.

"The patterns of pleiotropy we show through PheWAS for individual variants, trait-specific GRS, and pathway-partitioned GRS may help explain variants and pathways that increase susceptibility to more than one disease and thereby predispose to particular patterns of multimorbidity," the authors reported.