A previous study identified five of the genes associated with Alzheimer´s disease (AD) as differentially methylated in post-mortem brain samples from AD patients compared to controls(1). We sought to investigate whether the same associations could be found in leukocytes collected pre-mortem in dementia discordant twin pairs.
We measured DNA methylation levels in leukocytes from 427 twins using the Illumina 450K array, and selected CpG sites within SORL1 (n=51), ABCA7 (n=215), HLA-DRB5 (n=14), SLC24A4 (n=53), and BIN1 (n=68). Forty twin pairs discordant for dementia and 33 twin pairs discordant for AD were identified. Conditional logistic regression was used to compare differences in methylation levels at each CpG site between discordant pairs. In accordance with the previous study, the resulting p-values for individual CpGs in each locus were combined into a test statistic for the gene-wide significance using the Fisher product method. The statistical significance was assessed by random permutations, and hence a p-value for each gene was obtained.
We found a significant difference in methylation between dementia discordant pairs in SORL1 (sortilin related receptor 1, p=0.01), and between AD discordant pairs in BIN1 (bridging integrator 1, p=0.04). There was no difference in methylation levels in ABCA7, HLA-DRB5, or SLC24A4 between the discordant twins.
In conclusion, SORL1 and BIN1 are not only differentially methylated in cortical cells from AD patients compared to controls, but also in leukocytes collected pre-mortem from dementia discordant twin pairs. The importance of allelic variation as well as methylation variation, both in the CNS and the periphery, in dementia suggests that SORL1 and BIN1 are important in the disease process.
1. Yu L, Chibnik LB, Srivastava GP, et al. Association of Brain DNA Methylation in SORL1, ABCA7, HLA-DRB5, SLC24A4, and BIN1 With Pathological Diagnosis of Alzheimer Disease. JAMA neurology 2014.
Ageing , Cognition: Education, Intelligence, Memory, Attention
