The predictive power of profiling the DNA methylome in human health and disease

Abstract

Early and accurate diagnosis significantly improves the chances of disease survival. DNA methylation (5mC), the major DNA modification in the human genome, is now recognized as a biomarker of immense clinical potential. This is due to its ability to delineate precisely cell-type, quantitate both internal and external exposures, as well as tracking chronological and biological components of the aging process. Here, we survey the current state of DNA methylation as a biomarker and predictor of traits and disease. This includes Epigenome-wide association study (EWAS) findings that inform Methylation Risk Scores (MRS), EpiScore long-term estimators of plasma protein levels, and machine learning (ML) derived DNA methylation clocks. These all highlight the significant benefits of accessible peripheral blood DNA methylation as a surrogate measure. However, detailed DNA methylation biopsy analysis in real-time is also empowering pathological diagnosis. Furthermore, moving forward, in this multi-omic and biobank scale era, novel insights will be enabled by the amplified power of increasing sample sizes and data integration.

Keywords: DNA methylation; EWAS; Epigenetics; biological ageing; epigenetic clocks; epigenetic estimators; epigenomics; methylation risk scores.

Figure 1.

DNA methylation biomarkers. DNA methylation changes at specific CpG loci can be used as biomarkers for i) cell proportion deconvolution; ii) estimating disease risk via methylation risk scores (MRS); iii) environmental exposure estimators; iv) chronological and biological ageing clocks; v) diagnostic episignatures in genetic syndromes due to mutations in the epigenomic machinery genes. The DNA methylation cycle of active gain (via the DNMT enzyme; with DNMT3 being the de novo version) to 5mC; and loss through oxidation (via the TET enzyme) to 5hmC, 5fC and 5caC, followed by TDG excision, leaving an abasic site for the base excision repair (BER) pathway to install an unmodified Cytosine (C). Passive DNAm loss occurs through dilution when there is inaction of the maintenance DNMT (DNMT1) post replication.