DNA methylation variability in Alzheimer's disease

Highlights

• Conventional epigenetic analysis focuses on testing the mean difference in DNA methylation between cases and controls, but DNA methylation instability (e.g., increased variability) may also affect disease susceptibility.

• No study has examined the association of methylation variability with Alzheimer's disease.

• We identified genomic regions harboring variably methylated probes associated with Aβ plaques and neurofibrillary tangles.

• These regions are largely nonoverlapped with regions detected by mean methylation analysis, highlighting the importance of testing methylation variability in future research.

Abstract

DNA methylation plays a critical role in brain aging and Alzheimer's disease (AD). While prior studies have largely focused on testing mean DNA methylation, DNA methylation instability (quantified by DNA methylation variability) may also affect disease susceptibility. Using DNA methylation data collected by the Religious Orders Study and the Rush Memory and Aging Project, we identified 249 and 115 variably methylated probes (VMPs) associated with amyloid-β and neurofibrillary tangles, respectively. These VMPs clustered into 133 and 14 regions, respectively. Notably, we found that most of these VMPs did not overlap with differentially methylated probes, indicating that VMPs and differentially methylated probes may capture different sets of genes associated with AD pathology. Overall, our results demonstrated that DNA methylation instability affects AD neuropathology and highlights the importance of testing methylation variability in epigenetic research.

Introduction

Alzheimer's dementia is a devastating neurodegenerative disorder affecting over 35 million people worldwide, and this number is expected to nearly triple by 2050 (Duthey, 2013). Accumulation of extracellular amyloid-β and intraneuronal neurofibrillary tangles are the 2 hallmarks of Alzheimer's disease (AD). DNA methylation plays an important role in regulating gene expression, and altered DNA methylation has been implicated in AD pathology (Irier and Jin, 2012). Several epigenome-wide association studies (De Jager et al., 2014, Lunnon et al., 2014, Smith et al., 2018, Watson et al., 2016) identified differentially methylated probes (DMPs) and differentially methylated regions associated with AD. While previous studies have largely focused on testing the difference in mean DNA methylation level between patients and controls, recent evidence suggests that DNA methylation instability may also affect disease susceptibility (Palumbo et al., 2018). For example, several recent studies found that increased DNA methylation variability in multiple genes was associated with cancers (Hansen et al., 2011), type 1 diabetes (Paul et al., 2016), aging (Jones et al., 2015), and rheumatoid arthritis (Webster et al., 2018). This evidence suggests that, in addition to the mean change in DNA methylation, altered DNA methylation variability or instability of DNA methylation may also play an important role in disease pathophysiology. To date, we are not aware of any study that examined the role of DNA methylation variability in AD neuropathology. Using existing DNA methylation and gene expression data generated in postmortem prefrontal cortex of older individuals participating in 2 community-based population cohorts of aging and dementia (the Religious Orders Study and the Rush Memory and Aging Project [ROSMAP]) (Bennett et al., 2012b), we conducted analyses to examine whether altered DNA methylation stability contributes to AD pathology by identifying variably methylated probes (VMPs) and variably methylated regions (VMRs) in the postmortem brain tissue. For comparison purpose, we also examined the potential overlap between variably methylated genes (e.g., genes showing altered methylation variability) and differentially methylated genes (e.g., genes showing altered mean DNA methylation level) at a genome scale. Moreover, we assessed the impact of DNA methylation instability on gene expression profiled on the same brain cortex.