Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong...

Area of Science:

• Genomics
• Epigenetics
• Human Genetics

Background:

• Genetic variants influence phenotypes through epigenetic modifications like methylation quantitative trait loci (mQTLs).
• Correlated regions of systemic interindividual variation (CoRSIVs) are genomic regions with variable CpG methylation, measurable in blood DNA without cellular composition bias.

Purpose of the Study:

• To conduct the first large-scale assessment of mQTLs within human CoRSIVs.
• To investigate the relationship between DNA methylation in blood and internal organs, and its genetic underpinnings.

Main Methods:

• Target-capture bisulfite sequencing was employed to analyze DNA methylation at 4086 CoRSIVs across multiple tissues from 188 GTEx donors.
• Genetic influences on CoRSIV methylation were quantified, and mQTLs were identified and characterized.

Main Results:

• DNA methylation at CoRSIVs in blood strongly correlates with methylation and gene expression in internal organs.
• An unprecedented number of mQTLs were discovered at CoRSIVs, with genetic influences being exceptionally strong (median R²=0.76), yielding over 70-fold more mQTLs than previous studies.
• mQTLs at CoRSIVs exhibited highly skewed beta coefficients, suggesting a major allele predicts higher methylation, potentially linked to transposable elements and evolutionary selection.
• These mQTL polymorphisms were found to be associated with metabolic and other diseases through GWAS analyses.

Conclusions:

• Focusing on systemic interindividual epigenetic variants, particularly mQTLs within CoRSIVs, significantly enhances the discovery of genetic associations.
• This approach is expected to advance studies linking human epigenetic variation to disease risk.