Genome-wide DNA methylation profiling in nonagenarians suggests an effect of PM20D1 in late onset Alzheimer’s disease

Abstract

Background The aim of this study is to identify differentially methylated regions (DMRs) in the genomes of a sample of cognitively healthy individuals and a sample of individuals with LOAD, all of them nonagenarians from Costa Rica. Methods In this study, we compared whole blood DNA methylation profiles of 32 individuals: 21 cognitively healthy and 11 with LOAD, using the Infinium MethylationEPIC BeadChip. First, we calculated the epigenetic age of the participants based on Horvath’s epigenetic clock. DMRcate and Bumphunter were used to identify DMRs. After in silico and knowledge-based filtering of the DMRs, we performed a methylation quantitative loci (mQTL) analysis (rs708727 and rs960603). Results On average, the epigenetic age was 73 years in both groups, which represents a difference of over 20 years between epigenetic and chronological age in both affected and unaffected individuals. Methylation analysis revealed 11 DMRs between groups, which contain six genes and two pseudogenes. These genes are involved in cell cycle regulation, embryogenesis, synthesis of ceramides, and migration of interneurons to the cerebral cortex. One of the six genes is PM20D1, for which altered expression has been reported in LOAD. After genotyping previously reported mQTL SNPs for the gene, we found that average methylation in the PM20D1 DMR differs between genotypes for rs708727, but not for rs960603. Conclusions This work supports the possible role of PM20D1 in protection against AD, by showing differential methylation in blood of affected and unaffected nonagenarians. Our results also support the influence of genetic factors on PM20D1 methylation levels.

Epigenetic Peripheral Biomarkers for Early Diagnosis of Alzheimer’s Disease

“…In a following study, the authors further confirmed that frontal cortex PM20D1 DNA methylation and expression are significantly correlated with the AD pathology [ 73 ]. More recently, an investigation performed on the blood DNA of 32 nonagenarians individuals, including 21 cognitively healthy subjects and 11 AD patients, found that PM20D1 methylation was increased in AD individuals, and that methylation levels were associated with rs708727, but not with rs960603 [ 74 ]. These studies clearly highlight that the methylation status of PM20D1 is altered in AD, and that the methylation status is also dependent on the genetic background of the individuals.…”

The many roles of the Alzheimer-associated gene PM20D1

“…The levels of these NAAs are physiologically increased after cold exposure and cause an uncoupling of mitochondrial respiration in different peripheral tissues by directly interacting with mitochondrial proteins [10,24,25] . Mitochondrial uncoupling occurs when ATP is not produced through electron transport [26] , but redox energy is released in the form of heat, since protons are lost , immortalized B cells [6] , peripheral blood [7,8] [ [6][7][8] Hypomethylation/overexpression (close to diagnosis and in early disease)…”

“…Postmortem brain [5] , brain prefrontal cortex [6,7] , immortalized B cells [6] , peripheral blood [7,45] rs1172198 [5] rs708727 [5][6][7][8] rs823082 [5] rs823088 [5] rs1361754 [5] rs960603 [5,6] [ [5][6][7]45] Obesity (BMI) Hypomethylation Adipose tissue [36] , peripheral blood [52] rs823080 [36] [ 36,52]…”

“…Multiple recent studies have shown that PM20D1 expression is, at least in part, genetically determined. Six SNPs (rs1172198, rs708727, rs823082, rs823088, rs1361754, and rs960603), which are located downstream of the gene, have been shown to be associated with both PM20D1 methylation and expression levels and are thus considered methylation QTLs (mQTLs) as well as expression QTLs (eQTLs) [5][6][7][8]34] . These SNPs constitute a haplotype which plays a role in the methylation of the PM20D1 promoter and its expression.…”

“…There is growing evidence that differential methylation in this gene is associated with several heterogeneous disease phenotypes [Table 1]. Additionally, it was discovered that genetic variants close to but not inside the gene can influence methylation levels at the gene's promoter [5][6][7][8] , and this methylation correlates with expression [6] . It has been proposed that these variants had not been previously found in GWAS because the PM20D1 region is not well represented and is in low linkage disequilibrium with the SNPs included in the common microarrays used in GWAS [6] .…”