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

Li, Qingqin; Sun, Yu; Wang, Tania

doi:10.1186/s13148-020-00944-z

Cited by 57 publications

(40 citation statements)

References 76 publications

(105 reference statements)

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“…The top seven age-related genes further confirm that these changes are related toward aging biology. For example, ANK1 is differentially methylated during Alzheimer’s disease 63 and have genetic variants associated with a risk of type 2 diabetes 64 . NPAS3 and MEF2C are involved in neurodevelopment 65 , 66 .…”

Section: Discussionmentioning

confidence: 99%

Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Robeck

Fei

et al. 2021

Commun Biol

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The development of a precise blood or skin tissue DNA Epigenetic Aging Clock for Odontocete (OEAC) would solve current age estimation inaccuracies for wild odontocetes. Therefore, we determined genome-wide DNA methylation profiles using a custom array (HorvathMammalMethyl40) across skin and blood samples (n = 446) from known age animals representing nine odontocete species within 4 phylogenetic families to identify age associated CG dinucleotides (CpGs). The top CpGs were used to create a cross-validated OEAC clock which was highly correlated for individuals (r = 0.94) and for unique species (median r = 0.93). Finally, we applied the OEAC for estimating the age and sex of 22 wild Norwegian killer whales. DNA methylation patterns of age associated CpGs are highly conserved across odontocetes. These similarities allowed us to develop an odontocete epigenetic aging clock (OEAC) which can be used for species conservation efforts by provide a mechanism for estimating the age of free ranging odontocetes from either blood or skin samples.

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Section: Discussionmentioning

confidence: 99%

Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Robeck

Fei

et al. 2021

Commun Biol

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“…Patient brain samples with short post-mortem intervals (PMI), large numbers of slices located in the frontal and temporal cortex (by Brodmann’s area) were prioritized to ensure the homogeneity of samples for group-wise comparison in the study. Overlapping samples from the same cohort was also described in a recent epigenome-wide association study (EWAS) and a mRNA-Seq study ( Li et al, 2020 ; Li and De Muynck, 2021 ).…”

Section: Methodsmentioning

confidence: 97%

“…As described previously ( Li et al, 2020 ), genomic DNA and total RNA, including miRNA were simultaneously purified from brain tissue samples using the AllPrep DNA/RNA/miRNA Universal Kit (QIAGEN Inc., Germantown, MD, United States) following the manufacturer’s guidelines. Approximately 20–30 mg of tissue was used for each extraction.…”

Section: Methodsmentioning

confidence: 99%

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Integrated miRNA-Seq and mRNA-Seq Study to Identify miRNAs Associated With Alzheimer’s Disease Using Post-mortem Brain Tissue Samples

Cai

2021

Front. Neurosci.

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Alzheimer’s disease (AD), the leading form of dementia, is associated with abnormal tau and β-amyloid accumulation in the brain. We conducted a miRNA-seq study to identify miRNAs associated with AD in the post-mortem brain from the inferior frontal gyrus (IFG, n = 69) and superior temporal gyrus (STG, n = 81). Four and 64 miRNAs were differentially expressed (adjusted p-value < 0.05) in AD compared to cognitively normal controls in the IFG and STG, respectively. We observed down-regulation of several miRNAs that have previously been implicated in AD, including hsa-miR-212-5p and hsa-miR-132-5p, in AD samples across both brain regions, and up-regulation of hsa-miR-146a-5p, hsa-miR-501-3p, hsa-miR-34a-5p, and hsa-miR-454-3p in the STG. The differentially expressed miRNAs were previously implicated in the formation of amyloid-β plaques, the dysregulation of tau, and inflammation. We have also observed differential expressions for dozens of other miRNAs in the STG, including hsa-miR-4446-3p, that have not been described previously. Putative targets of these miRNAs (adjusted p-value < 0.1) were found to be involved in Wnt signaling pathway, MAPK family signaling cascades, sphingosine 1-phosphate (S1P) pathway, adaptive immune system, innate immune system, and neurogenesis. Our results support the finding of dysregulated miRNAs previously implicated in AD and propose additional miRNAs that appear to be dysregulated in AD for experimental follow-up.

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“…Because of their propensity to epigenetic alterations such as hypermethylation, GCC-repeats are mutation hotspots 14,15 , and this may be the reason why this class of repeats do not expand beyond certain lengths unless when selected, such as in gene regulatory regions 16 . Expansions of GCC repeats in the 5′ UTR of a number of genes is associated with hypermethylation and intellectual disability 17 .…”

Section: Discussionmentioning

confidence: 99%

Novel biological implication of a strictly monomorphic GCC repeat in the human PRKACB gene

Khamse¹,

Jafarian²,

Bozorgmehr³

et al. 2021

Preprint

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Across human protein-coding genes, PRKACB (Protein Kinase CAMP-Activated Catalytic Subunit Beta) contains one of the longest GCC-repeats, and is predominantly expressed in the brain. Here we studied this STR in 300 human subjects, consisting of late-onset neurocognitive disorder (NCD) (N = 150) and controls (N = 150). We also studied the impact of this STR on the three-dimensional structure of DNA. While the PRKACB GCC-STR was strictly monomorphic at 7-repeats, we detected two 7/8 genotypes only in the NCD group. In comparison to all other lengths, (GCC)7 had the least effect on the three-dimensional structure of DNA, evidenced by minimal divergence between 0 and 7-repeats (divergence score = 0.04) and significant divergence between 0 and 8 repeats (divergence score = 0.50). A similar inert effect to the GCC-repeat was not detected in other classes of STRs such as GA and CA repeats. In conclusion, we report monomorphism of an exceptionally long GCC repeat in the PRKACB gene in human, its inert effect on DNA structure, and divergence in two cases of late-onset NCD. This is the first indication of natural selection for an exceptionally long monomorphic GCC-repeat, which probably evolved to function as an “epigenetic knob”, without changing the regional DNA structure.

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

Cited by 57 publications

References 76 publications

Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Multi-species and multi-tissue methylation clocks for age estimation in toothed whales and dolphins

Integrated miRNA-Seq and mRNA-Seq Study to Identify miRNAs Associated With Alzheimer’s Disease Using Post-mortem Brain Tissue Samples

Novel biological implication of a strictly monomorphic GCC repeat in the human PRKACB gene

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