DNA methylation of candidate imprint control regions associated with Alzheimer’s disease in Non‐Hispanic Blacks and Non‐Hispanic Whites

Abstract

AbstractBackgroundThere are more than 55 million people with dementia worldwide, and it is estimated that currently 6.5 million people are living with Alzheimer’s disease (AD) in the United States. AD exhibits racial disparities whereby the prevalence is 2‐fold higher in Non‐Hispanic Blacks (NHB) compared to Non‐Hispanic Whites (NHW). It is hypothesized that epigenetics and aberrant imprinting caused by early life exposure to adverse environmental agents may contribute to AD risk later in life, although to date a comprehensive assessment of the imprinting state of the genome in AD‐affected populations has not been reported.MethodsTo address this hypothesis, we investigated cytosine methylation at candidate imprint control regions (ICRs) in post‐mortem tissues (brain) of nine AD cases (5NHB, 4NHW) and eight controls (4NHB, 4NHW), using whole genome bisulfite sequencing. Furthermore, we performed a limited clinical study in which blood samples from six individuals, three AD patients (2NHB, 1NHW) and three controls (all NHB), were subjected to methyl‐sequencing. These data were analyzed against an expanded set of candidate ICRs previously described by our group (i.e., human imprintome) to identify regions of the genome exhibiting aberrant methylation in AD patients compared to controls.ResultsWe found differential methylation in DNA derived from post‐mortem tissues of AD cases compared to controls overlapping with the expanded set of ICRs in the human imprintome (79 in NHBs and 27 in NHWs), including candidate ICR on chromosome 17 near the NLRP1 inflammasome gene (5771207‐5771575; Hg38). When extended to blood from extant controls and patients, our analysis identified a single nucleotide polymorphism (CA → CG; rs12451480) within the candidate ICR on chromosome 17, that distinguishes controls (CA) from AD patients (CG), and in which the cytosine is methylated.ConclusionWe demonstrate concordance between the methylation state of post‐mortem brain‐ and blood‐derived DNA distinguishing controls from AD patients. Furthermore, the discovery of a SNP differentiating controls from AD patients, within a candidate ICR that alters its methylation state, is consistent with an aberrant imprinting phenomenon. Our results support the hypothesis that aberrant imprinting, as can result from adverse exposures during early development, may contribute to later risk of AD.