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PreprintCited by 57Epigenetics and DNA MethylationDementia and Cognitive Impairment ResearchAlzheimer's disease research and treatments

Cross-tissue meta-analysis of blood and brain epigenome-wide association studies in Alzheimer’s disease

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Silva, Tiago C., Young, Juan I., Zhang, Lanyu, Gomez, Lissette, Schmidt, Michael A., Varma, Achintya, Chen, X. Steven, Martin, Eden R. +1 more·2022·Nature Communications
DOI 10.1101/2022.04.11.22273748PMC PMC9388493

Preprint — published as 10.1038/s41467-022-32475-x

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Abstract

We performed a meta-analysis of two large independent blood-based Alzheimer’s disease (AD) epigenome-wide association studies, the ADNI and AIBL studies, and identified 5 CpGs, mapped to the SPIDR, CDH6 genes, and intergenic regions, that were significantly associated with AD diagnosis. A cross-tissue analysis that combined these blood DNA methylation datasets with four additional methylation datasets prioritized 97 CpGs and 10 genomic regions that are significantly associated with both AD neuropathology and AD diagnosis. Our integrative analysis revealed expressions levels of 13 genes and 10 pathways were significantly associated with the AD-associated methylation differences in both brain and blood, many are involved in the immune responses in AD, such as the CD79A, LY86, SP100, CD163, CD200 , and MS4A1 genes and the neutrophil degranulation, antigen processing and presentation, interferon signaling pathways. An out-of-sample validation using the AddNeuroMed dataset showed the best performing logistic regression model included age, sex, cell types and methylation risk score based on prioritized CpGs from cross-tissue analysis (AUC = 0.696, 95% CI: 0.616 - 0.770, P- value = 2.78 × 10 −5 ). Our study provides a valuable resource for future mechanistic and biomarker studies in AD.

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  • The meta-analysis was expected to be underpowered given modest sex-specific sample sizes, so CpGs at P < 1×10−5 were also prioritized.

    “Based on our experiences and previous studies in the analysis of EWAS measured in blood [22, 38, 47], we expected our meta-analysis to be underpowered, given the modest sample sizes of the sex-specific analyses. Therefore, we also prioritized CpGs with suggestive significance at the pre-specified significance threshold of P-value < 1×10−5.”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [22]

    The Discussion reports that only five CpGs reached 5% FDR in the paper’s blood-sample meta-analysis, so the authors examined 45 more at P < 10⁻⁵; it also discusses ways to improve the power of blood-based methylation studies. The paper does not attribute limited power to modest sex-specific sample sizes. In the citing sentence, that sex-specific rationale and the decision to prioritize CpGs describe the citing authors’ own analysis, rather than a finding of this source. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • 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 [22]

    The introduction says DNA methylation plays an important role in AD, and the Discussion reports methylation differences between AD subjects and cognitively normal subjects. The paper does not establish the broader claim that methylation alterations are involved in many diseases. (LLM, conf=0.85)

    Experimental — accuracy not yet measured

  • Many of the sex-specific effects were missed in the previous sex-combined analysis because of cancellation of effects in different directions or dilution from samples with no effect.

    “Because of the cancelation of effects in different directions, or dilution from samples with no effect, many of the sex-specific effects were missed in our previous sex-combined analysis [22].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [22]

    The Blood sample meta-analysis section (page unavailable) describes an AD methylation analysis that included sex as a covariate, supporting its identification as the previous sex-combined analysis. Our copy does not report that many sex-specific effects were missed or establish cancellation or dilution as the reason. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • This is consistent with previous studies in AD that found DNA methylation variations in the blood, by and large, did not recapitulate those in the brain.

    “consistent with previous studies in AD that also found DNA methylation variations in the blood, by and large, did not recapitulate those in the brain [20, 22, 93].”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [22]

  • In comparison with the previous sex-combined analysis of AIBL and ADNI EWAS, a small number of AD-associated CpGs and DMRs were identified by both analyses: 4/23 CpGs and 1/41 DMRs in females, and 1/4 CpGs and 3/24 DMRs in males.

    “The comparison with our previous sex-combined analysis of AIBL and ADNI EWAS [22] showed a small number of AD-associated CpGs and DMRs (4/23 CpGs and 1/41 DMRs in females, 1/4 CpGs, and 3/24 DMRs in males), including the DMR located in the promoter of the PM20D1 gene we described above, were identified by both analyses (Supplementary Tables 2, 3, and 5)”

    From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [22]

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Cited by

Sorted by citations

Authors
Silva, T. C., Young, J. I., Zhang, L., Gomez, L., Schmidt, M. A., Varma, A., Chen, X. S., Martin, E. R., & Wang, L.
Affiliations
University of Miami (US)
Corresponding author
Wang, Lily
ORCID
Venue
Nature Communications
Publisher
openRxiv
Published
2022-04-12
Volume
13
Issue
1
Pages
4852-4852
ISSN
2041-1723 (ISSN-L)
DOI
10.1101/2022.04.11.22273748
PMC
PMC9388493
OpenAlex
W4292242322
Cited by
57
References
1
Citations by year
2026: 11 · 2025: 17 · 2024: 12 · 2023: 13 · 2022: 4
FWCI
1.20
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Nature Communications (publishedVersion, cc-by)
  • medRxiv (acceptedVersion, cc-by-nc-nd)
  • 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 Defense (U01 AG024904, W81XWH, W81XWH-12-2-, W81XWH-12, W81XWH1220012, AG024904)
  • Foundation for the National Institutes of Health (P30AG10161, W81XWH-12-2-0012, R01AG17917, U01AG024904, Grant U01 AG024904, R01AG15819, AG024904)
  • U.S. Department of Health and Human Services (R01AG060472, R01AG061127, R21AG060459, R01AG062634)
  • Alzheimer's Association (R01 AG17917, P30AG10161, R01 AG15819, U01 AG024904, U01 AG46152, W81XWH-12-2-0012)
  • Bristol-Myers Squibb (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Eli Lilly and Company (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Pfizer (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • Illinois Department of Public Health (P30AG10161, R01AG15819, R01AG17917, R01AG30146)
  • Biogen (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • University of Southern California (W81XWH-12-2-0012, U01 AG024904)
  • F. Hoffmann-La Roche (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Meso Scale Diagnostics (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • Alzheimer's Disease Neuroimaging Initiative (W81XWH-12-2–0012, U01AG024904, AG024904, W81XWH-12-2-, Department of Defense award number W81XWH-12-2-0012)
  • BioClinica (U01 AG024904, W81XWH-12-2-0012, AG024904)
  • Novartis Pharmaceuticals Corporation (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Rush University (P30AG10161, R01 AG15819, R01AG30146)
  • Northern California Institute for Research and Education (U01 AG024904, W81XWH-12-2-0012)
  • Translational Genomics Research Institute
  • Eisai (W81XWH-12-2-0012, U01 AG024904, AG024904)
  • Servier (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • H. Lundbeck A/S (U01 AG024904, AG024904, W81XWH-12-2-0012)
  • IXICO (AG024904, W81XWH-12-2-0012, U01 AG024904)
  • National Institutes of Health (1rf1ag061127-01, 3u01ag024904-10s2, W81XWH, W81XWH-12-2-0012, U01-AG024904, Grant U01 AG024904, AG024904)
  • Genentech (W81XWH-12-2-0012, AG024904, U01 AG024904)
  • Canadian Institutes of Health Research (U01AG46152, R01AG17917, U01 AG024904, R01AG15819, W81XWH-12-2-0012, P30AG10161)
  • National Institute on Aging (U01-AG-024904, R01AG017917, P30-AG 10161, U01 AG32984, R01AG030146, R01 AG30146, W81XWH-12-2–0012, R01‐AG17917, R01 AG15819, R01-AG36836, R01AG036836, AG 024904, U01AG046152, R01AG061127, R01AG015819, 1R01AG060472, P30AG010161, U01AG032984, R01 AG060472, RF1 AG061127, U01‐AG46152, R01AG062634, R21AG060459)
  • National Institute of Neurological Disorders and Stroke (RF1NS128145)
  • National Institute of Biomedical Imaging and Bioengineering (W81XWH-12-2-0012, U01 AG024904, AG024904)
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, epigenome-wide association study, CDH6, methylation biomarkers, immune cell proportions, methylation risk score, ADNI, AIBL
MeSH terms
Epigenome, Alzheimer Disease, Brain, Humans, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study

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