Abstract
As the world's population ages, the age-related cognitive decline presents a great challenge to world's healthcare systems. One of the molecular mechanisms implicated in cognitive ageing is DNA methylation, an epigenetic modification known to be a key player in memory formation, maintenance, and synaptic plasticity. Using the twin design we performed an epigenome-wide association study (EWAS) in a population of 486 middle-aged monozygotic twins (mean age at follow-up 65.9, SD = 6.1) and correlated their blood DNA methylation to their level (cross-sectional analysis) and change in cognitive abilities over 10 years (longitudinal analysis). We identified several CpG sites where cross-sectional cognitive functioning was associated with DNA methylation levels. The top identified loci were located in ZBTB46 (p = 5.84 × 10−7), and TAF12 (p = 4.91 × 10−7). KEGG's enrichment analyses of the most associated findings identified “Neuroactive ligand-receptor interaction” as the most enriched pathway (p = 0.0098). Change in cognitive functioning over 10 years was associated with DNA methylation levels in AGBL4 (p = 9.01 × 10−7) and SORBS1 (p = 5.28 × 10−6), with the first gene playing an important role in neuronal survival and the latter gene implicated before in Alzheimer's disease and ischemic stroke. Our findings point to an association between changes in DNA methylation of genes related to neuronal survival and change of cognitive functioning in aging individuals.
Highlights
The age-related cognitive decline is suggested to be caused by a combination of subtle and selective, region-specific changes resulting from alterations in dendritic morphology, cellular connectivity, Ca2+ homeostasis, gene expression and other factors altogether affecting neuronal plasticity (Burke and Barnes, 2006; Tripathi, 2012; Morrison and Baxter, 2014)
Maintenance of DNA methylation in the human genome across life depends mainly on two groups of enzymes: DNA methyltransferases (DNMTs), responsible for the addition of methyl group to the 5th position of cytosine, and ten-eleven translocation (TET) family enzymes that catalyze oxidation of 5-methylcytosine to forms further removed by base excision repair and substituted back with an unmodified cytosine (Chen and Riggs, 2011; Kohli and Zhang, 2013)
For the paired analysis regressing intra-pair difference in DNA methylation on intra-pair difference in cognition at followup resulted in five probes with p < 10−5 with cg05867245, mapping to the Zinc Finger And BTB Domain Containing 46 gene (ZBTB46), being the most associated finding with p = 5.84 × 10−7 (Table 1)
Summary
The age-related cognitive decline is suggested to be caused by a combination of subtle and selective, region-specific changes resulting from alterations in dendritic morphology, cellular connectivity, Ca2+ homeostasis, gene expression and other factors altogether affecting neuronal plasticity (Burke and Barnes, 2006; Tripathi, 2012; Morrison and Baxter, 2014). Along the human life age-related changes in DNA methylation seem to be driven by two mechanisms: epigenetic clock and epigenetic drift, where the first phenomena describes functional age-related epigenetic changes at specific sites of the genome common across individuals, while the latter one relates to the global decrease in stability and precision of DNA methylation with age (Jones et al, 2015) These genome-wide changes in DNA methylation levels are complex and tend to increase with age in regions known for their low methylation, e.g., promoter-associated CpG islands, but decrease in regions with high DNA methylation, e.g., intergenic non-island CpG sites, leading to a global loss of methylation in the genome (Illingworth and Bird, 2009; Heyn et al, 2012). Decrease in Tet expression in neural progenitor cells was associated with aberrant promoter hypermethylation of genes associated with regulation of adult neurogenesis (Zhang et al, 2013) All these studies point to the important role of DNA methylation in cognitive functioning and age-related cognitive decline
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