Abstract
BackgroundGrowing evidence shows that epigenetic modifications play a role in Alzheimer’s disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples.ResultsSamples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina© Infinium MethylationEPIC BeadChip. Five and 14 differentially methylated positions (DMPs) associated with pathology (i.e., Braak stage) with p value less than Bonferroni correction threshold of 6.79 × 10–8 in the STG and IFG were identified, respectively. These cytosine–phosphate–guanine (CpG) sites included promoter associated cg26263477 annotated to ABCA7 in the STG (p = 1.21 × 10–11), and cg14058329 annotated to the HOXA5/HOXA3/HOXA-AS3 gene cluster (p = 1.62 × 10–9) and cg09448088 (p = 3.95 × 10–9) annotated to MCF2L in the IFG. These genes were previously reported to harbor DMPs and/or differentially methylated regions (DMRs). Previously reported DMPs annotated to RMGA, GNG7, HOXA3, GPR56, SPG7, PCNT, RP11-961A15.1, MCF2L, RHBDF2, ANK1, PCNT, TPRG1, and RASGEF1C were replicated (p < 0.0001). One hundred twenty-one and 173 DMRs associated with pathology in the STG and IFG, respectively, were additionally identified. Of these, DMRs annotated to 30 unique genes were also identified as significant DMRs in the same brain region in a recent meta-analysis, while additional DMRs annotated to 12 genes were reported as DMRs in a different brain region or in a cross-cortex meta-analysis. The significant DMRs were enriched in promoters, CpG islands, and exons in the genome. Gene set enrichment analysis of DMPs and DMRs showed that gene sets involved in neuroinflammation (e.g., microglia differentiation), neurogenesis, and cognition were enriched (false discovery rate (FDR) < 0.05).ConclusionsTwenty-two DMPs and 30 DMRs associated with pathology were replicated, and novel DMPs and DMRs were discovered.
Highlights
Dementia refers to conditions of memory loss and other cognitive decline serious enough to interfere with daily life
Fourteen CpG probes were associated with pathology in the inferior frontal gyrus (IFG), including CpG probes cg14058329 annotated to the HOXA5/HOXA3/HOX-AS3 gene cluster (p = 1.62 × 10–9) and cg09448088 (p = 3.95 × 10–9) annotated to MCF2L (Fig. 1). cg09448088 was recently reported as a significant Differentially methylated position (DMP) in an cross-cortex Braak stage epigenome-wide association study (EWAS) meta-analysis [21], and the HOXA gene cluster was reported to harbor DMPs and Differentially methylated region (DMR) associated with Braak stage [20, 21]
We conducted a modest size EWAS to identify DMPs and DMRs associated with pathology
Summary
Dementia refers to conditions of memory loss and other cognitive decline serious enough to interfere with daily life. Genome-wide association studies (GWAS) have identified dozens of loci for late onset AD (LOAD) [3,4,5,6,7,8,9]. Growing evidence shows that epigenetic modifications play a role in AD onset and progression [12,13,14,15]. Epigenome-wide association studies (EWAS) using bisulfite conversion approaches coupled with the Illumina Infinium® HumanMethylation450 BeadChip have demonstrated robust and reproducible differences in total DNA methylation at a number of loci in AD brain [17,18,19,20,21,22], including ankyrin 1 (ANK1), ABCA7, BIN1, TREM2, and the HOXA and HOXB gene clusters. Growing evidence shows that epigenetic modifications play a role in Alzheimer’s disease (AD). We performed an epigenome-wide association study (EWAS) to evaluate the DNA methylation differences using postmortem superior temporal gyrus (STG) and inferior frontal gyrus (IFG) samples
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