The interest of this working group are epigenetic processes that regulate gene expression via modifications to DNA, histone proteins, and chromatin.
Ammar Al-Chalabi, Ahmad Al Kheilfat, Andrea Calvo, Antonia Ratti, Vincenzo Silani
Despite success in identifying genetic variants associated with ALS, in many cases there remains uncertainty about the specific involved in disease pathogenesis and how their function is regulated. Insights into the functional complexity of the genome have also focused attention on the probable role of non-sequence-based genomic variation in health and disease. Of particular interest are epigenetic processes that regulate gene expression via modifications to DNA, histone proteins, and chromatin. DNA methylation is the best-characterized epigenetic modification, stably influencing gene expression via disruption of transcription factor binding and recruitment of methyl-binding proteins that initiate chromatin compaction and gene silencing. Despite being traditionally regarded as a mechanism of transcriptional repression, DNA methylation is actually associated with both increased and decreased gene expression, and other genomic functions including alternative splicing and promoter usage. The availability of high-throughput profiling methods for quantifying DNA methylation across the genome at single-base resolution in large numbers of samples has enabled researchers to perform epigenome-wide association studies (EWAS) aimed at identifying methylomic variation associated with environmental exposure and disease; however, these studies are inherently more complex to design and interpret than GWAS. The dynamic nature of epigenetic processes means that unlike in genetic epidemiology a range of potentially important confounding factors need to be considered, including tissue or cell type, age, sex, lifestyle exposures, and reverse causation. This WG will identify epigenetic variation in clinical cases, discordant MZ twins, and post-mortem brain tissue, integrating methylomic data with genetic and available environmental data.