Unidirectional and Bidirectional Causation between Smoking and Blood DNA Methylation: Evidence from Twin-based...

Area of Science:

• Epigenetics
• Genomics
• Behavioral Science

Background:

• Cigarette smoking is linked to DNA methylation (DNAm) changes, presumed to cause adverse health effects.
• Previous Mendelian Randomisation (MR) studies found limited evidence for smoking's causal effect on DNAm.

Purpose of the Study:

• To investigate the causal relationship between current smoking and blood DNAm using an integrated MR and twin causal model approach.
• To explore potential bidirectional causality between DNA methylation and smoking liability.

Main Methods:

• Utilized data from the Netherlands Twin Register (N=2577).
• Employed combined Mendelian Randomisation (MR) and twin causal models.
• Used multiallelic/polygenic scores as instrumental variables, controlling for horizontal pleiotropy.

Main Results:

• Identified potential causal effects of current smoking on DNAm at >500 loci, enriched in pathways like hemopoiesis and immune regulation.
• Found evidence of reverse and bidirectional causality, where DNAm variation may influence smoking liability.
• Discovered specific gene-regulatory elements in the brain linked to DNAm influencing smoking, and identified genes involved in G protein-coupled receptor signaling and innate immunity.

Conclusions:

• This study provides robust evidence for causal links between current smoking and blood DNAm.
• Highlights the complex interplay, including bidirectional effects, between DNA methylation and smoking behavior.
• Demonstrates the utility of twin studies with genotypic and DNAm data for causal inference in epigenetics and health.