Smoking, DNA Methylation, and Lung Function: a Mendelian Randomization Analysis to Investigate Causal Pathways

Area of Science:

• Genetics and Epigenetics
• Respiratory Medicine
• Biostatistics

Background:

• Smoking is a major risk factor for reduced lung function.
• The role of DNA methylation, a key epigenetic mechanism, in mediating smoking's effect on lung function requires further investigation.
• Understanding these relationships can identify novel therapeutic targets.

Purpose of the Study:

• To investigate the causal effect of smoking-associated DNA methylation on lung function (FEV1).
• To determine if DNA methylation mediates the impact of smoking on lung function.
• To explore shared genetic variants between lung function, DNA methylation, and gene expression.

Main Methods:

• Two-sample Mendelian randomization (MR) was employed using large UK Biobank and SpiroMeta Consortium datasets.
• Two-step MR was used to assess mediation by DNA methylation.
• A multiple-trait colocalization ('moloc') framework was utilized to identify shared causal variants.

Main Results:

• Evidence suggests a potential causal effect of DNA methylation on FEV1 at 18 CpG sites.
• Replication confirmed causal effects at three specific CpG sites (cg21201401, cg19758448, cg12616487).
• DNA methylation did not clearly mediate smoking's effect on FEV1, but some sites may influence lung function via smoking.
• Shared causal variants were identified between lung function, gene expression, and DNA methylation.

Conclusions:

• Specific DNA methylation sites show potential causal links to lung function.
• Findings suggest potential therapeutic targets for enhancing lung function and aiding smoking cessation.
• Further research with larger, tissue-specific datasets is needed for confirmation.