CoChat
Sign Up
Cited by 139Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Epigenome-wide meta-analysis of DNA methylation differences in prefrontal cortex implicates the immune processes in Alzheimer’s disease

Open access
Zhang, Lanyu, Silva, Tiago C., Young, Juan I., Gomez, Lissette, Schmidt, Michael A., Hamilton-Nelson, Kara L., Kunkle, Brian W., Chen, Xi +2 more·2020·Nature Communications
DOI 10.1038/s41467-020-19791-wPMC PMC7704686
Open this paper in CoChat — free accountOpen PDF

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1038/s41467-020-19791-w

Cites

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Alterations in DNA methylation levels are involved in many diseases, including AD.

    “Alterations of DNA methylation levels have been shown to be involved in many diseases, including AD [19–24].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [21]

    The Results report DNA methylation differences in people with pathological AD, and the Discussion describes their potential roles in AD. The paper does not establish the broader claim about many diseases; its findings concern AD. It also reports associations rather than demonstrating that the methylation changes cause disease. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Alterations of DNA methylation levels have been implicated in multiple neurological disorders including AD.

    “Importantly, alterations of DNA methylation levels have also been implicated in multiple neurological disorders including AD [18–22]”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [22]

    The Introduction states that there is growing evidence for a role of DNA methylation in AD, and the Discussion reports methylation differences in pathological AD. This supports the AD example, but the paper does not establish the broader claim about multiple neurological disorders. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Similarly, in the analysis of male samples, among FDR significant differences, 58 (76%) CpGs and 15 DMRs (56%), mapped to genes such as MAMSTR, RHBDF2, and AGAP2, overlapped with significant hits from sex-combined meta-analysis.

    “Similarly, in the analysis of male samples, among FDR significant differences, 58 (76%) CpGs and 15 DMRs (56%), mapped to genes such as MAMSTR, RHBDF2, and AGAP2, overlapped with significant hits from sex-combined meta-analysis [22]”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [22]

    The Results section on sample matching reports overlap with the main analysis and names MAMSTR and AGAP2 among genes significant in both analyses. But that analysis matched cases and controls by sex and age; it does not report a male-only analysis or the claimed overlaps of 58 (76%) CpGs and 15 (56%) DMRs. No page number is available in our copy. (LLM, conf=0.78)

    Experimental — accuracy not yet measured

  • The authors previously meta-analyzed four brain sample datasets and identified CpGs and DMRs, many involved in immune processes, significantly associated with AD neuropathology.

    “We previously meta-analyzed these four brain sample datasets and identified a number of CpGs and DMRs, many involved in immune processes, that are significantly associated with AD neuropathology [21, 36].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [21]

  • DNA methylation is an important epigenetic modification that regulates gene transcription and is involved in Alzheimer's disease.

    “DNA methylation is an important epigenetic modification that regulates gene transcription and is known to be involved in AD”

    From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [22]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

The citation lists haven’t been fetched yet

References 98 · Cited by 139

Research works printed but not linked: 68

  1. [3]Kunkle BW Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Abeta, tau, immunity and lipid processing Nat. Genet. 2019 51 414 430 10.1038/s41588-019-0358-2 30820047 PMC6463297 · DOI · Paper page
  2. [4]Yokoyama AS Rutledge JC Medici V DNA methylation alterations in Alzheimer’s disease Environ. Epigenet. 2017 3 dvx008 10.1093/eep/dvx008 29492310 PMC5804548 · DOI
  3. [5]Liu X Jiao B Shen L The epigenetics of Alzheimer’s disease: factors and therapeutic implications Front. Genet. 2018 9 579 10.3389/fgene.2018.00579 30555513 PMC6283895 · DOI
  4. [6]Qazi TJ Quan Z Mir A Qing H Epigenetics in Alzheimer’s disease: perspective of DNA methylation Mol. Neurobiol. 2018 55 1026 1044 10.1007/s12035-016-0357-6 28092081 · DOI · Paper page
  5. [7]Klein HU Bennett DA De Jager PL The epigenome in Alzheimer’s disease: current state and approaches for a new path to gene discovery and understanding disease mechanism Acta Neuropathol. 2016 132 503 514 10.1007/s00401-016-1612-7 27573688 PMC5189639 · DOI · Paper page
  6. [9]Teschendorff AE Relton CL Statistical and integrative system-level analysis of DNA methylation data Nat. Rev. Genet. 2018 19 129 147 10.1038/nrg.2017.86 29129922 · DOI
  7. [10]Mallik S An evaluation of supervised methods for identifying differentially methylated regions in Illumina methylation arrays Brief. Bioinform. 2019 20 2224 2235 10.1093/bib/bby085 30239597 PMC6954393 · DOI
  8. [11]Irizarry RA Comprehensive high-throughput arrays for relative methylation (CHARM) Genome Res. 2008 18 780 790 10.1101/gr.7301508 18316654 PMC2336799 · DOI
  9. [12]Pedersen BS Schwartz DA Yang IV Kechris KJ Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P-values Bioinformatics 2012 28 2986 2988 10.1093/bioinformatics/bts545 22954632 PMC3496335 · DOI · Paper page
  10. [13]Gomez L coMethDMR: accurate identification of co-methylated and differentially methylated regions in epigenome-wide association studies with continuous phenotypes Nucleic Acids Res. 2019 47 e98 10.1093/nar/gkz590 31291459 PMC6753499 · DOI
  11. [16]Gasparoni G DNA methylation analysis on purified neurons and glia dissects age and Alzheimer’s disease-specific changes in the human cortex Epigenet. Chromat. 2018 11 41 10.1186/s13072-018-0211-3 PMC6058387 30045751 · DOI · Paper page
  12. [17]Joehanes R Epigenetic signatures of cigarette smoking Circ. Cardiovasc. Genet. 2016 9 436 447 10.1161/CIRCGENETICS.116.001506 27651444 PMC5267325 · DOI
  13. [18]Chen YA Discovery of cross-reactive probes and polymorphic CpGs in the illumina infinium humanmethylation450 microarray Epigenetics 2013 8 203 209 10.4161/epi.23470 23314698 PMC3592906 · DOI
  14. [19]Watson CT Genome-wide DNA methylation profiling in the superior temporal gyrus reveals epigenetic signatures associated with Alzheimer’s disease Genome Med. 2016 8 5 10.1186/s13073-015-0258-8 26803900 PMC4719699 · DOI · Paper page
  15. [20]Bakulski KM Genome-wide DNA methylation differences between late-onset Alzheimer’s disease and cognitively normal controls in human frontal cortex J. Alzheimers Dis. 2012 29 571 588 10.3233/JAD-2012-111223 22451312 PMC3652332 · DOI · Paper page
  16. [21]Ernst J Kellis M ChromHMM: automating chromatin-state discovery and characterization Nat. Methods 2012 9 215 216 10.1038/nmeth.1906 22373907 PMC3577932 · DOI
  17. [22]Yen A Kellis M Systematic chromatin state comparison of epigenomes associated with diverse properties including sex and tissue type Nat. Commun. 2015 6 7973 10.1038/ncomms8973 26282110 PMC4557131 · DOI · Paper page
  18. [23]Chadwick LH The NIH roadmap epigenomics program data resource Epigenomics 2012 4 317 324 10.2217/epi.12.18 22690667 PMC3381455 · DOI
  19. [24]Sheffield NC Bock C LOLA: enrichment analysis for genomic region sets and regulatory elements in R and Bioconductor Bioinformatics 2016 32 587 589 10.1093/bioinformatics/btv612 26508757 PMC4743627 · DOI
  20. [25]Consortium EP An integrated encyclopedia of DNA elements in the human genome Nature 2012 489 57 74 10.1038/nature11247 22955616 PMC3439153 · DOI · Paper page
  21. [26]Reddington JP Redistribution of H3K27me3 upon DNA hypomethylation results in de-repression of Polycomb target genes Genome Biol. 2013 14 R25 10.1186/gb-2013-14-3-r25 23531360 PMC4053768 · DOI · Paper page
  22. [27]Brinkman AB Sequential ChIP-bisulfite sequencing enables direct genome-scale investigation of chromatin and DNA methylation cross-talk Genome Res. 2012 22 1128 1138 10.1101/gr.133728.111 22466170 PMC3371717 · DOI · Paper page
  23. [28]Hon GC Global DNA hypomethylation coupled to repressive chromatin domain formation and gene silencing in breast cancer Genome Res. 2012 22 246 258 10.1101/gr.125872.111 22156296 PMC3266032 · DOI · Paper page
  24. [32]Cunningham C Microglia and neurodegeneration: the role of systemic inflammation Glia 2013 61 71 90 10.1002/glia.22350 22674585 · DOI · Paper page
  25. [33]Yu L Methylation profiles in peripheral blood CD4+ lymphocytes versus brain: the relation to Alzheimer’s disease pathology Alzheimer’s Dement. 2016 12 942 951 10.1016/j.jalz.2016.02.009 27016692 PMC5014706 · DOI
  26. [35]Edgar RD Jones MJ Meaney MJ Turecki G Kobor MS BECon: a tool for interpreting DNA methylation findings from blood in the context of brain Transl. Psychiatry 2017 7 e1187 10.1038/tp.2017.171 28763057 PMC5611738 · DOI · Paper page
  27. [36]McCarthy S A reference panel of 64,976 haplotypes for genotype imputation Nat. Genet. 2016 48 1279 1283 10.1038/ng.3643 27548312 PMC5388176 · DOI · Paper page
  28. [39]Guo H Integration of disease association and eQTL data using a Bayesian colocalisation approach highlights six candidate causal genes in immune-mediated diseases Hum. Mol. Genet. 2015 24 3305 3313 10.1093/hmg/ddv077 25743184 PMC4498151 · DOI
  29. [40]Vassar R ADAM10 prodomain mutations cause late-onset Alzheimer’s disease: not just the latest FAD Neuron 2013 80 250 253 10.1016/j.neuron.2013.09.031 24139026 PMC4090694 · DOI · Paper page
  30. [41]van Iterson M van Zwet EW Consortium B Heijmans BT Controlling bias and inflation in epigenome- and transcriptome-wide association studies using the empirical null distribution Genome Biol. 2017 18 19 10.1186/s13059-016-1131-9 28129774 PMC5273857 · DOI · Paper page
  31. [45]Teschendorff AE A beta-mixture quantile normalization method for correcting probe design bias in Illumina Infinium 450 k DNA methylation data Bioinformatics 2013 29 189 196 10.1093/bioinformatics/bts680 23175756 PMC3546795 · DOI
  32. [46]Liu Y Wang M Marcora EM Zhang B Goate AM Promoter DNA hypermethylation—implications for Alzheimer’s disease Neurosci. Lett. 2019 711 134403 10.1016/j.neulet.2019.134403 31351091 PMC6759378 · DOI
  33. [48]Huentelman MJ Calmodulin-binding transcription activator 1 (CAMTA1) alleles predispose human episodic memory performance Hum. Mol. Genet. 2007 16 1469 1477 10.1093/hmg/ddm097 17470457 · DOI
  34. [49]Ramanan VK FASTKD2 is associated with memory and hippocampal structure in older adults Mol. Psychiatry 2015 20 1197 1204 10.1038/mp.2014.142 25385369 PMC4427556 · DOI
  35. [50]Stock AJ Kasus-Jacobi A Pereira HA The role of neutrophil granule proteins in neuroinflammation and Alzheimer’s disease J. Neuroinflamm. 2018 15 240 10.1186/s12974-018-1284-4 PMC6112130 30149799 · DOI
  36. [52]Brock AJ The antimicrobial protein, CAP37, is upregulated in pyramidal neurons during Alzheimer’s disease Histochem Cell Biol. 2015 144 293 308 10.1007/s00418-015-1347-x 26170148 PMC4575391 · DOI
  37. [54]Liu PP Xu YJ Teng ZQ Liu CM Polycomb repressive complex 2: emerging roles in the central nervous system Neuroscientist 2018 24 208 220 10.1177/1073858417747839 29283025 · DOI
  38. [55]Yu JR Lee CH Oksuz O Stafford JM Reinberg D PRC2 is high maintenance Genes Dev. 2019 33 903 935 10.1101/gad.325050.119 31123062 PMC6672058 · DOI
  39. [57]Deevy, O. & Bracken, A. P. PRC2 functions in development and congenital disorders. Development146, dev181354 (2019). PMC6803372 31575610
  40. [59]Wang X Molecular analysis of PRC2 recruitment to DNA in chromatin and its inhibition by RNA Nat. Struct. Mol. Biol. 2017 24 1028 1038 10.1038/nsmb.3487 29058709 PMC5771497 · DOI
  41. [60]Riising EM Gene silencing triggers polycomb repressive complex 2 recruitment to CpG islands genome wide Mol. Cell 2014 55 347 360 10.1016/j.molcel.2014.06.005 24999238 · DOI
  42. [61]Choufani, S. et al. DNA methylation signature for EZH2 functionally classifies sequence variants in three PRC2 complex genes. Am. J. Hum. Genet.106, 596–610 (2020). PMC7212265 32243864
  43. [62]Mohn F Lineage-specific polycomb targets and de novo DNA methylation define restriction and potential of neuronal progenitors Mol. Cell 2008 30 755 766 10.1016/j.molcel.2008.05.007 18514006 · DOI
  44. [64]Gal-Yam EN Frequent switching of Polycomb repressive marks and DNA hypermethylation in the PC3 prostate cancer cell line Proc. Natl Acad. Sci. USA 2008 105 12979 12984 10.1073/pnas.0806437105 18753622 PMC2529074 · DOI
  45. [67]Efthymiou AG Goate AM Late onset Alzheimer’s disease genetics implicates microglial pathways in disease risk Mol. Neurodegener. 2017 12 43 10.1186/s13024-017-0184-x 28549481 PMC5446752 · DOI · Paper page
  46. [68]Zhang B Integrated systems approach identifies genetic nodes and networks in late-onset Alzheimer’s disease Cell 2013 153 707 720 10.1016/j.cell.2013.03.030 23622250 PMC3677161 · DOI · Paper page
  47. [69]Sekar S Alzheimer’s disease is associated with altered expression of genes involved in immune response and mitochondrial processes in astrocytes Neurobiol. Aging 2015 36 583 591 10.1016/j.neurobiolaging.2014.09.027 25448601 PMC4315763 · DOI · Paper page
  48. [70]Kiddle SJ Candidate blood proteome markers of Alzheimer’s disease onset and progression: a systematic review and replication study J. Alzheimers Dis. 2014 38 515 531 10.3233/JAD-130380 24121966 · DOI
  49. [74]Gjoneska E Conserved epigenomic signals in mice and humans reveal immune basis of Alzheimer’s disease Nature 2015 518 365 369 10.1038/nature14252 25693568 PMC4530583 · DOI · Paper page
  50. [75]Mokalled MH Johnson AN Creemers EE Olson EN MASTR directs MyoD-dependent satellite cell differentiation during skeletal muscle regeneration Genes Dev. 2012 26 190 202 10.1101/gad.179663.111 22279050 PMC3273842 · DOI
  51. [76]Lim JH Kim HG Park SK Kang CJ The promoter of the Immunoglobulin J Chain gene receives its authentic enhancer activity through the abutting MEF2 and PU.1 sites in a DNA-looping interaction J. Mol. Biol. 2009 390 339 352 10.1016/j.jmb.2009.05.040 19467243 · DOI
  52. [77]Gosselin D Environment drives selection and function of enhancers controlling tissue-specific macrophage identities Cell 2014 159 1327 1340 10.1016/j.cell.2014.11.023 25480297 PMC4364385 · DOI · Paper page
  53. [78]Esposito M Sherr GL Epigenetic modifications in Alzheimer’s neuropathology and therapeutics Front. Neurosci. 2019 13 476 10.3389/fnins.2019.00476 31133796 PMC6524410 · DOI
  54. [79]Ciechomska, M., Roszkowski, L. & Maslinski, W. DNA methylation as a future therapeutic and diagnostic target in rheumatoid arthritis. Cells8, 953 (2019). PMC6770174 31443448
  55. [80]Smith AR Parallel profiling of DNA methylation and hydroxymethylation highlights neuropathology-associated epigenetic variation in Alzheimer’s disease Clin. Epigenet. 2019 11 52 10.1186/s13148-019-0636-y PMC6429761 30898171 · DOI
  56. [81]Zhao J A genome-wide psrofiling of brain DNA hydroxymethylation in Alzheimer’s disease Alzheimer’s Dement. 2017 13 674 688 10.1016/j.jalz.2016.10.004 28089213 PMC6675576 · DOI
  57. [82]Ellison EM Bradley-Whitman MA Lovell MA Single-base resolution mapping of 5-hydroxymethylcytosine modifications in hippocampus of Alzheimer’s disease subjects J. Mol. Neurosci. 2017 63 185 197 10.1007/s12031-017-0969-y 28866733 PMC5909840 · DOI
  58. [83]Lardenoije R Alzheimer’s disease-associated (hydroxy)methylomic changes in the brain and blood Clin. Epigenet. 2019 11 164 10.1186/s13148-019-0755-5 PMC6880587 31775875 · DOI
  59. [84]Bennett DA Religious orders study and rush memory and aging project J. Alzheimers Dis. 2018 64 S161 S189 10.3233/JAD-179939 29865057 PMC6380522 · DOI · Paper page
  60. [85]Braak H Braak E Staging of Alzheimer’s disease-related neurofibrillary changes Neurobiol. Aging 1995 16 271 278 10.1016/0197-4580(95)00021-6 7566337 · DOI · Paper page
  61. [86]Dedeurwaerder S A comprehensive overview of infinium human methylation450 data processing Brief. Bioinform. 2014 15 929 941 10.1093/bib/bbt054 23990268 PMC4239800 · DOI
  62. [87]Reese SE Epigenome-wide meta-analysis of DNA methylation and childhood asthma J. Allergy Clin. Immunol. 2019 143 2062 2074 10.1016/j.jaci.2018.11.043 30579849 PMC6556405 · DOI
  63. [88]Wang T A systematic study of normalization methods for Infinium 450K methylation data using whole-genome bisulfite sequencing data Epigenetics 2015 10 662 669 10.1080/15592294.2015.1057384 26036609 PMC4623491 · DOI
  64. [90]Du P Comparison of Beta-value and M-value methods for quantifying methylation levels by microarray analysis BMC Bioinform. 2010 11 587 10.1186/1471-2105-11-587 PMC3012676 21118553 · DOI · Paper page
  65. [91]Guintivano J Aryee MJ Kaminsky ZA A cell epigenotype specific model for the correction of brain cellular heterogeneity bias and its application to age, brain region and major depression Epigenetics 2013 8 290 302 10.4161/epi.23924 23426267 PMC3669121 · DOI
  66. [92]Higgins JP Thompson SG Quantifying heterogeneity in a meta-analysis Stat. Med. 2002 21 1539 1558 10.1002/sim.1186 12111919 · DOI · Paper page
  67. [93]Rice K Higgins J Lumley T A re-evaluation of fixed effect(s) meta-analysis J. R. Stat. Soc. A 2018 181 205 227 10.1111/rssa.12275 · DOI · Paper page
  68. [97]Phipson B Maksimovic J Oshlack A missMethyl: an R package for analyzing data from Illumina’s HumanMethylation450 platform Bioinformatics 2016 32 286 288 10.1093/bioinformatics/btv560 26424855 · DOI

Authors
Zhang, L., Silva, T. C., Young, J. I., Gomez, L., Schmidt, M. A., Hamilton-Nelson, K. L., Kunkle, B. W., Chen, X., Martin, E. R., & Wang, L.
Affiliations
University of Miami (US)
Corresponding author
Wang, Lily
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2020-11-30
Volume
11
Issue
1
Pages
6114-6114
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-19791-w
PMC
PMC7704686
OpenAlex
W3107160482
Cited by
139
References
98
Citations by year
2026: 13 · 2025: 29 · 2024: 20 · 2023: 29 · 2022: 19 · 2021: 26 · 2020: 3
FWCI
1.89
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
U.S. Department of Health & Human Services | NIH | National Institute on Aging (R21AG060459, R01AG061127, R01AG062634, R01AG060472)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
Alzheimer's disease, DNA methylation, prefrontal cortex, differentially methylated regions, Braak stages, MEF2C, PU.1, immune processes, polycomb repressive complex 2, biomarkers
MeSH terms
Aged, Aged, 80 and over, Alzheimer Disease, Brain, Carrier Proteins, Female, Humans, Immunity, Transcription Factors, Prefrontal Cortex, DNA Methylation, GTP-Binding Proteins, GTPase-Activating Proteins, Tumor Suppressor Proteins, Epigenesis, Genetic, Gene Regulatory Networks, Genome-Wide Association Study, MEF2 Transcription Factors

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review