Identification of Cell-Free DNA Methylation Signatures as a Potential Genomic Biomarker of Alzheimer’s Disease
Abstract – Alzheimer’s Disease (AD) is a progressive, neurodegenerative disease that leads to brain atrophy and neuronal apoptosis. A necessity for a noninvasive and efficient diagnostic method for early detection and monitoring of AD still persists in the healthcare community. Minimal insight has been obtained regarding the use of circulating cell-free DNA (ccfDNA) to analyze epigenetic signatures in the brain; herein, we aim to assess cfDNA methylation signatures as potential biomarkers for AD. In the proposed methodology, cell-free DNA from 1 AD patient and 1 Control patient was extracted, bisulfite converted, and processed for Whole Genome Bisulfite Sequencing (WGBS). The computational analysis of WGBS libraries was performed on HGCC (Human Genetics Compute Cluster), and the following computations were performed: FastQC analysis, Data Trimming, WGBS Reads Mapping, Methylation Calling, Differentially Methylated Regions (DMRs) identification, and DMR annotation. Finally, Gene Ontology (GO) analysis was conducted to identify enriched biological pathways associated with DMRs-associated genes. 10,848 DMRs, composed of 2,615 hypermethylated DMRs and 8,233 hypomethylated DMRs, were identified. The GO analysis revealed multiple neurological process associations for DMRs-associated genes. The biological processes of nervous system development, neuron differentiation, axon guidance, and neuron migration were enriched for many genes containing hypomethylated DMRs; in comparison, some hypermethylated DMRs-related genes were involved in brain development and modulation of synaptic transmission processes. These GO enriched biological processes indicate that cfDNA methylation signatures can reflect methylation alteration of some critical genes involved in brain development and could be potential markers of AD.