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

Authors: GUNASEKARA, CHATHURA - Children'S Nutrition Research Center (CNRC); MACKAY, HARRY - Children'S Nutrition Research Center (CNRC); SCOTT, C. ANTHONY - Children'S Nutrition Research Center (CNRC); LI, SHAOBO - University Of Southern California; LARITSKY, ELEONORA - Children'S Nutrition Research Center (CNRC); BAKER, MARIA - Children'S Nutrition Research Center (CNRC); GRIMM, SANDRA - Baylor College Of Medicine; JUN, GOO - University Of Texas Health Science Center; LI, YUEMI - Baylor College Of Medicine; CHEN, RUI - Baylor College Of Medicine; WIEMELS, JOSEPH - University Of Southern California; COARFA, CRISTIAN - Baylor College Of Medicine; WATERLAND, ROBERT - Children'S Nutrition Research Center (CNRC)

Submitted to: Genome Biology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 12/1/2022
Publication Date: 1/12/2023
Citation: Gunasekara, C., MacKay, H., Scott, C., Li, S., Laritsky, E., Baker, M., Grimm, S.L., Jun, G., Li, Y., Chen, R., Wiemels, J.L., Coarfa, C., Waterland, R.A. 2023. Systemic interindividual epigenetic variation in humans is associated with transposable elements and under strong genetic control. Genome Biology. 24. Article 2. https://doi.org/10.1186/s13059-022-02827-3.
DOI: https://doi.org/10.1186/s13059-022-02827-3

Interpretive Summary: Epigenetics is a system for molecular marking of DNA – it tells the different cells in the body which genes to turn on or off in that cell type. There is great interest in understanding epigenetic causes of disease. But the cell-specific nature of epigenetics makes it challenging to study. Whereas a blood sample can be used to 'genotype' an individual, most epigenetic marks in blood DNA provide no clues about epigenetic dysregulation in other parts of the body, such as the brain or heart. We focused on the most stable form of epigenetic regulation – DNA methylation – which occurs at sites in the genome called CpG sites. To overcome the obstacle of tissue specificity, in 2019 we reported our discovery of CoRSIVs, special regions of the genome in which a blood sample can be used to infer epigenetic regulation throughout the body. In this latest study we performed a large-scale validation of CoRSIVs and demonstrated the feasibility of studying these regions at the population level. We designed an Agilent SureSelect reagent to target 4086 human CoRSIVs and performed target-capture bisulfite sequencing (a quantitative method for DNA methylation analysis) in multiple tissues from each of 188 donors from the NIH Gene-Tissue Expression (GTEx) program. Our results validated systemic interindividual epigenetic variation at CoRSIVs. Moreover, we used GTEx genome sequence data on the donors to quantify genetic influences on DNA methylation (termed mQTL). Shockingly, our relatively small study of under 200 individuals discovered 72 times more mQTL than had previously been known (even compared to a study of 33,000 individuals). This is because the Illumina DNA methylation arrays that the field of population epigenetics has relied upon for the last decade are flawed: ~95% of the CpG sites assayed by the platform do not show appreciable interindividual variation in humans. Because interindividual variance is necessary not just for mQTL detection but also for population epigenetics, our findings will inevitably lead to a paradigm shift in epigenetic epidemiology.

Technical Abstract: Genetic variants can modulate phenotypic outcomes via epigenetic intermediates, for example at methylation quantitative trait loci (mQTL). We present the first large-scale assessment of mQTL at human genomic regions selected for interindividual variation in CpG methylation, which we call correlated regions of systemic interindividual variation (CoRSIVs). These can be assayed in blood DNA and do not reflect interindividual variation in cellular composition. We use target-capture bisulfite sequencing to assess DNA methylation at 4086 CoRSIVs in multiple tissues from each of 188 donors in the NIH Gene-Tissue Expression (GTEx) program. At CoRSIVs, DNA methylation in peripheral blood correlates with methylation and gene expression in internal organs. We also discover unprecedented mQTL at these regions. Genetic influences on CoRSIV methylation are extremely strong (median R2=0.76), cumulatively comprising over 70-fold more human mQTL than detected in the most powerful previous study. Moreover, mQTL beta coefficients at CoRSIVs are highly skewed (i.e., the major allele predicts higher methylation). Both surprising findings are independently validated in a cohort of 47 non-GTEx individuals. Genomic regions flanking CoRSIVs show long-range enrichments for LINE-1 and LTR transposable elements; the skewed beta coefficients may therefore reflect evolutionary selection of genetic variants that promote their methylation and silencing. Analyses of GWAS summary statistics show that mQTL polymorphisms at CoRSIVs are associated with metabolic and other classes of disease. A focus on systemic interindividual epigenetic variants, clearly enhanced in mQTL content, should likewise benefit studies attempting to link human epigenetic variation to the risk of disease.