A genome-wide analysis of brain DNA methylation identifies newcandidate genes for sporadic amyotrophic lateral sclerosis

摘要

Genetic variants may underlie sporadic amyotrophic lateral sclerosis (SALS), but in only a few percent of patients havecausative mutations been found. This is possibly because SALS is more often due to a variation in DNA methylation, anepigenetic phenomenon involved in gene silencing. Methylation across the whole genome was examined in brain DNA of 10SALS patients and 10 neurologically-normal controls. Methylated DNA was immunoprecipitated and interrogated byAffymetrix GeneChip Human Tiling 2.0R Arrays. Methylation levels were compared between SALS patients and controlsat each region of methylation across the genome. SALS patients had either hypo- or hyper-methylation at 38 methylationsites (p <0.01). Of these, 23 were associated with genes and three with CpG islands. Pathway analysis showed that geneswith different methylation in SALS were particularly involved in calcium homeostasis, neurotransmission and oxidativestress. In conclusion, a number of genes, either unsuspected in SALS or in potential cell death pathways, showed alteredmethylation in SALS brains. The possibility of epigenetic therapy for SALS should encourage confirmation of these initialresults in a future larger whole-genome DNA methylation study.