Alzheimer's loci: epigenetic associations and interaction with genetic factors
Open accessAbstract
Objective: We explore the role of DNA methylation in Alzheimer's disease ( AD ). To elucidate where DNA methylation falls along the causal pathway linking risk factors to disease, we examine causal models to assess its role in the pathology of AD . Methods: DNA methylation profiles were generated in 740 brain samples using the Illumina HumanMet450K beadset. We focused our analysis on CpG sites from 11 AD susceptibility gene regions. The primary outcome was a quantitative measure of neuritic amyloid plaque ( NP ), a key early element of AD pathology. We tested four causal models: (1) independent associations, (2) CpG mediating the association of a variant, (3) reverse causality, and (4) genetic variant by CpG interaction. Results: Six genes regions (17 CpGs) showed evidence of CpG associations with NP , independent of genetic variation – BIN 1 (5), CLU (5), MS 4A6A (3), ABCA 7 (2), CD 2 AP (1), and APOE (1). Together they explained 16.8% of the variability in NP . An interaction effect was seen in the CR 1 region for two CpGs, cg10021878 ( P = 0.01) and cg05922028 ( P = 0.001), in relation to NP . In both cases, subjects with the risk allele rs6656401 AT / AA display more methylation being associated with more NP burden, whereas subjects with the rs6656401 TT protective genotype have an inverse association with more methylation being associated with less NP . Interpretation: These observations suggest that, within known AD susceptibility loci, methylation is related to pathologic processes of AD and may play a largely independent role by influencing gene expression in AD susceptibility loci.
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The limited commonality between genetic and epigenetic loci in AD could be due to low power in EWAS and/or GWAS but could also reflect relatively independent roles of genetic variants and DNA methylation in influencing AD susceptibility.
“The limited commonality between genetic and epigenetic loci in AD could be due to the low power in EWAS and/or GWAS but could also reflect the relatively independent roles of genetic variants and DNA methylation in influencing AD susceptibility [65, 66].”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [66]
The Introduction and Abstract Interpretation say that genetic variation and DNA methylation may have largely independent roles in AD pathology and susceptibility. The Introduction also says stringent multiple-comparison criteria limited an earlier methylome-wide analysis. However, the paper does not establish the claimed limited commonality between genetic and epigenetic loci or specifically attribute it to low power in EWAS and/or GWAS. No page numbers are available in our copy. (LLM, conf=0.85)
Experimental — accuracy not yet measuredTargeted studies have revealed methylation alterations at additional loci associated with disease.
“Targeted studies have revealed methylation alterations at additional loci associated with disease [195–197]”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [197]
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Cites
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Flagged first, then by citations
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Cited by
Sorted by citations
Genetic architecture of Alzheimer's disease
Neuner, S. M., TCW, J., & Goate, A. M. (2020) · Neurobiology of Disease · doi:10.1016/j.nbd.2020.104976 · Cited by 126 · see citing works
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Distinct sex-specific DNA methylation differences in Alzheimer’s disease
C. Silva, T., Zhang, W., Young, J. I., Gomez, L., Schmidt, M. A., Varma, A., Chen, X. S., Martin, E. R., & Wang, L. (2022) · Alzheimer's Research & Therapy · doi:10.1186/s13195-022-01070-z · Cited by 33 · see citing works
“The limited commonality between genetic and epigenetic loci in AD could be due to the low power in EWAS and/or GWAS but could also reflect the relatively independent roles of genetic variants and DNA methylation in influencing AD susceptibility [65, 66].”
Background
- Authors
- Chibnik, L. B., Yu, L., Eaton, M. L., Srivastava, G., Schneider, J. A., Kellis, M., Bennett, D. A., & De Jager, P. L.
- Affiliations
- Broad Institute (US)
- Rush University Medical Center (US)
- Program in Translational NeuroPsychiatric Genomics Institute for the Neurosciences Departments of Neurology and Psychiatry Brigham and Women's Hospital Boston Massachusetts 02115
- ORCID
- Venue
- Annals of Clinical and Translational Neurology
- Publisher
- Wiley
- Published
- 2015-04-24
- Volume
- 2
- Issue
- 6
- Pages
- 636-647
- ISSN
- 2328-9503 (ISSN-L)
- PMC
- PMC4479524
- OpenAlex
- W2083357269
- Cited by
- 60
- References
- 6
- Citations by year
- 2026: 2 · 2025: 2 · 2024: 1 · 2023: 5 · 2022: 4 · 2021: 5 · 2020: 8 · 2019: 10 · 2018: 9 · 2017: 5 · 2016: 5 · 2015: 3 · 2014: 1
- FWCI
- 5.40
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Annals of Clinical and Translational Neurology (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- Funders
- National Institutes of Health (P30AG10161, R01AG15819, R01AG17917, R01AG36042, R01AG36836, U01AG46152)
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- 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
- Keywords
- Alzheimer's disease, DNA methylation, epigenetics, genetic-epigenetic interaction, reverse causality, mediation analysis, BIN1, clusterin, MS4A6A, ABCA7, CD2AP, apolipoprotein E, complement receptor 1, brain tissue, gene expression
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