Previously, a perfectly-penned study uncovered a type of DNA methylation variation “written” in the genome, which varies from person to person but remains consistent across tissues. Deciphering these “CoRSIV” (correlated regions of systemic interindividual variation) notes supported a deeper understanding of epigenetic variance and the impact on disease, with blood DNA methylation profiles from these regions reflecting the epigenetic roots of disease in harder-to-access organs. In the latest edition of this gripping research, the CoRSIV story has taken a genetic twist with a “novel” finding.
A capable crew of writers led by Cristian Coarfa and Robert A. Waterland (Baylor College of Medicine, Houston) now follow-up by investigating the correlation between genetic and transcriptional variation and site-specific DNA methylation (methylation quantitative trait loci or mQTL) at ~4000 CoRSIVs using target-capture bisulfite sequencing in a range of tissues from 188 donors in collaboration with the NIH Genotype-Tissue Expression (GTEx) program.
Let’s hear about how Gunasekara and colleagues deciphered CoRSIV notes into “novel” findings:
- Analysis in human tissues validates ~4000 CoRSIVs as systemic individual variants (i.e., epigenetic polymorphisms)
- DNA methylation at gene-associated CoRSIVs in the blood correlate with DNA methylation and gene expression in internal organs, which is of interest to epigenetic epidemiology
- The analysis also uncovers “unprecedented” levels of mQTL at CoRSIVs, with strong genetic influences on CoRSIV methylation (over 70-fold more mQTL than noted in a previous study of 33,000 people), and highly skewed mQTL beta coefficients at CoRSIVs (meaning the major allele associates with higher methylation)
- Analysis of a separate cohort of 47 individuals independently validates this pair of surprising findings
- Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements
- Therefore, skewed beta coefficients may reflect the evolutionary selection of genetic variants that promote DNA methylation and silencing effects
- Analyses of genome-wide association studies also reveal an association of mQTL polymorphisms at CoRSIVs with human genetic variants that influence the risk/heritability of various classes of diseases (including metabolic)
Overall, the scribes of this epigenetic study highlight the importance of CoRSIVs when linking human epigenetic variation to disease risk and underscore the need to improve CoRSIV coverage to enhance the utility of commercially available tools for population epigenetics studies. The following steps in this research include the provision of human CoRSIV-capture reagents to the rest of the field and identifying human CoRSIVs in various ancestry groups.
“Population variance is essential not only for mQTL detection, but also for detecting associations between DNA methylation and risk of disease,” shares co-senior author Cristian Coarfa. Co-senior author Robert A. Waterland concludes, “We hope that the new tool we’ve developed will accelerate progress in understanding epigenetic causality of disease.”
For more on how notes in CoRSIV writing became a “novel,” see Genome Biology, January 2023.