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Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.

ABSTRACT: BACKGROUND: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. RESULTS:Samples 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?

SUBMITTER: Li QS

PROVIDER: S-EPMC7568396 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.

Li Qingqin S QS Sun Yu Y Wang Tania T

Clinical epigenetics 20201017 1

<h4>Background</h4>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.<h4>Results</h4>Samples from 72 AD patients and 62 age-matched cognitively normal controls were assayed using Illumina<sup>©</sup> Infinium MethylationEPIC BeadChip. Five and 14 differentially methyl ...[more]

PMID: 33069246

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Project description:Age-related changes in DNA methylation have been implicated in cellular senescence and longevity, yet the causes and functional consequences of these variants remain unclear. To elucidate the role of age-related epigenetic changes in healthy ageing and potential longevity, we tested for association between whole-blood DNA methylation patterns in 172 female twins aged 32 to 80 with age and age-related phenotypes. Twin-based DNA methylation levels at 26,690 CpG-sites showed evidence for mean genome-wide heritability of 18%, which was supported by the identification of 1,537 CpG-sites with methylation QTLs in cis at FDR 5%. We performed genome-wide analyses to discover differentially methylated regions (DMRs) for sixteen age-related phenotypes (ap-DMRs) and chronological age (a-DMRs). Epigenome-wide association scans (EWAS) identified age-related phenotype DMRs (ap-DMRs) associated with LDL (STAT5A), lung function (WT1), and maternal longevity (ARL4A, TBX20). In contrast, EWAS for chronological age identified hundreds of predominantly hyper-methylated age DMRs (490 a-DMRs at FDR 5%), of which only one (TBX20) was also associated with an age-related phenotype. Therefore, the majority of age-related changes in DNA methylation are not associated with phenotypic measures of healthy ageing in later life. We replicated a large proportion of a-DMRs in a sample of 44 younger adult MZ twins aged 20 to 61, suggesting that a-DMRs may initiate at an earlier age. We next explored potential genetic and environmental mechanisms underlying a-DMRs and ap-DMRs. Genome-wide overlap across cis-meQTLs, genotype-phenotype associations, and EWAS ap-DMRs identified CpG-sites that had cis-meQTLs with evidence for genotype-phenotype association, where the CpG-site was also an ap-DMR for the same phenotype. Monozygotic twin methylation difference analyses identified one potential environmentally-mediated ap-DMR associated with total cholesterol and LDL (CSMD1). Our results suggest that in a small set of genes DNA methylation may be a candidate mechanism of mediating not only environmental, but also genetic effects on age-related phenotypes.

Dataset Information

Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.

Publications

Epigenome-wide association study of Alzheimer's disease replicates 22 differentially methylated positions and 30 differentially methylated regions.

Similar Datasets

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