Abstract
DNA methylation differences in Alzheimer’s disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. Using a uniform analysis pipeline, we identified 3751 CpGs and 119 differentially methylated regions (DMRs) significantly associated with Braak stage. Our analysis identified differentially methylated genes such as MAMSTR, AGAP2, and AZU1. The most significant DMR identified is located on the MAMSTR gene, which encodes a cofactor that stimulates MEF2C. Notably, MEF2C cooperates with another transcription factor, PU.1, a central hub in the AD gene network. Our enrichment analysis highlighted the potential roles of the immune system and polycomb repressive complex 2 in pathological AD. These results may help facilitate future mechanistic and biomarker discovery studies in AD.
Highlights
DNA methylation differences in Alzheimer’s disease (AD) have been reported
After eliminating CpGs associated with smoking[17] or overlapping with cross-reactive probes[18], we obtained 3751 significant CpGs (Supplementary Data 1), of which 47.8% is located in noncoding regions
We conducted a comprehensive meta-analysis of four cohorts of prefrontal cortex brain samples to prioritize consistent DNA methylation differences involved in pathological AD
Summary
DNA methylation differences in Alzheimer’s disease (AD) have been reported. Here, we conducted a meta-analysis of more than 1000 prefrontal cortex brain samples to prioritize the most consistent methylation differences in multiple cohorts. In the Lunnon et al epigenome-wide association study (EWAS)[8], which examined postmortem brain tissues in pathological AD subjects and controls, the absolute difference in corrected DNA methylation between individuals with the lowest (score 0) and highest (score VI) Braak score ranged from 1 to 5% change even for the most significant CpGs in the prefrontal cortex region, a region that shows considerable vulnerability to AD. Because of methodological differences used for analyzing different methylation datasets, inconsistencies are often seen across multiple studies[9,10] To address these challenges, we conducted a meta-analysis of 1030 prefrontal cortex samples. Enrichment analysis of differentially methylated genes highlighted multiple immune processes epigenetically associated with pathological AD as well as polycomb repressed regions
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
