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DNA Methylation at Certain Sites May Have Causal Effect on Lung Function, Study Finds

NEW YORK – DNA methylation at certain sites of the genome influence lung function, an effect that may occur through its effect on cigarette smoking, a new study has found.

Smoking is a major risk factor for lung disease, which is often preceded by a decline in lung function. As smoking is also associated with a number of methylation-level alterations, researchers led by the University of Bristol's Rebecca Richmond sought to examine whether these methylation changes are also linked to lung function.

Using a Mendelian randomization approach followed by a multiple-trait colocalization framework and replication analysis, she and her colleagues found a causal effect for DNA methylation at three CpG sites on lung function. As they reported in the American Journal of Human Genetics Thursday, the researchers also uncovered evidence that there are shared causal variants among lung function, gene expression, and DNA methylation.

"These findings highlight potential therapeutic targets for improving lung function and possibly smoking cessation, although larger, tissue-specific datasets are required to confirm these results," the researchers wrote. 

In 2016, the CHARGE Consortium conducted a large epigenome-wide association study meta-analysis to find more than 2,600 cytosine-phosphate-guanine sites (CpGs) that differed between current smokers and never smokers. Of these CpG sites previously associated with smoking, Richmond and her colleagues identified 474 CpGs with methylation quantitative trait locus at the middle age time point in the ARIES dataset.

Using lung-function genome-wide association study summary data from 321,047 individuals from the UK Biobank — where lung function was measured by forced expiratory volume in one second — the researchers identified 18 CpGs that appear to affect lung function. These sites were associated with genes involved in a range of functions, including neurological development, apoptosis, and tumor suppression.

When they repeated that analysis in the SprioMeta cohort of 79,055 individuals, the researchers replicated associations at three CpGs with lung function: cg21201401 near LIME1/ZGPAT, cg19758448 near PGAP3, and cg12616487 near EML3/AHNAK. While the links at the other 15 CpGs could not be replicated, there was a consistency of effect for the majority of the CpG sites.

The researchers also examined the direction of causality to find there was little evidence that lung function had a causal effect on DNA methylation at any of those 18 CpG sites. 

Instead, there was evidence for a causal effect of DNA methylation at a number of these CpG sites on lifetime smoking. Still, they noted there was evidence that at some CpG sites, methylation there influenced lung function through its effect on smoking.

Using a multiple-trait colocalization framework and mQTL data from ARIES, lung function GWAS summary data from the UK Biobank, and eQTL data from the eQTLGen Consortium, the researchers further found evidence of shared causal variants between lung function, gene expression, and DNA methylation at five CpG sites. This suggests that the relationship between DNA methylation at those spots and lung function could affect the transcription of nearby genes.

These sites, the researchers noted, could be possible therapeutic targets, but they noted that larger-scale and more tissue-specific work was needed.