Genome-wide screening identifies DNA methylation sites that regulate the blood proteome

Area of Science:

• Genomics
• Proteomics
• Systems Biology

Background:

• Understanding DNA methylation's role in regulating blood protein levels is crucial for biomedical research.
• Epigenetic modifications, like DNA methylation, significantly influence gene expression and protein production.

Purpose of the Study:

• To conduct a genome-wide search for DNA methylation sites that affect protein levels.
• To identify specific genomic regions controlling multiple protein abundances.
• To develop a publicly available tool for disease-related methylation site discovery.

Main Methods:

• Genome-wide association study (GWAS) approach to link DNA methylation sites with protein quantitative trait loci (pQTLs).
• Bioinformatic analysis to identify 'hotspot' genomic regions impacting multiple proteins.
• Development of a Unix-based software for identifying disease-associated methylation sites and their protein targets.

Main Results:

• Identified 165 significant DNA methylation sites associated with 138 distinct proteins.
• Discovered 'hotspot' genomic regions, such as the ABO locus, regulating numerous proteins (e.g., 37 proteins) and linked to cardiometabolic diseases and SARS-CoV-2 severity.
• Demonstrated the software's utility by linking innate immunity components to systolic blood pressure.

Conclusions:

• This study provides a comprehensive catalog of DNA methylation sites regulating the human blood proteome.
• The developed freeware offers a valuable resource for researchers investigating epigenetic mechanisms in disease.
• Findings highlight the potential of epigenome-wide association studies in uncovering novel disease pathways and therapeutic targets.