The DOI matches its Crossref record; 62 of the 62 references it cites were found in a registry or an index.
Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
Open accessAbstract
We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.
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“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 [19]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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 [18]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“Consistent with previous studies [18, 19, 86, 87], we observed the majority of these sex-specific differences were hyper-methylated in samples with AD neuropathology, for which methylation levels increased as the AD Braak stage increased”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [18]
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“dysregulated DNAm has been observed as an early feature of AD neuropathology in the brain [19]”
From Distinct sex-specific DNA methylation differences in Alzheimer’s disease (2022) · cites this paper as [19]
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“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 [18]
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“Notably, none of the 14 CpGs detected in our interaction analysis was identified in previous large-scale DNA methylation studies [18–22]”
From Sex-specific DNA methylation differences in Alzheimer’s disease pathology (2021) · cites this paper as [18]
In the citing paper
“These reference epigenomes, combined with other genomics data, have provided functional and causal insights about several human disease (De Jager et al., 2014; Farh et al., 2015; Yao, Tak, Berman, & Farnham, 2014).”
From Integrative Analysis of Multi-omics Data for Discovery and Functional Studies of Complex Human Diseases (2016) · cites this paper as De Jager et al., 2014
In the citing paper
“The most significant GWAS SNP was also a significant eQTL with the same direction of effect as in CMC for FURIN (rs4702: P = 1 × 10−6), CLCN3 (rs10520163: P = 9 × 10−6), and SNAP91 (rs3798869: P = 3 × 10−4); TSNARE1 (rs4129585: P = 0.057) and CNTN4 (rs17194490: P = 0.07) also had alleles in the same direction of effect as in CMC but did not reach significance.”
From Gene expression elucidates functional impact of polygenic risk for schizophrenia (2016) · cites this paper as [26]
In the citing paper
“and two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology [198, 199].”
From Genetic architecture of Alzheimer's disease (2020) · cites this paper as [199]
In the citing paper
“A different study found altered methylation in the BIN1 locus at cg22883290 in relation to neuritic amyloid plaques and a pathologic diagnosis of AD, and this altered methylation pattern was independent of the effect of the rs744373 susceptibility variant [14].”
From BIN1 protein isoforms are differentially expressed in astrocytes, neurons, and microglia: neuronal and astrocyte BIN1 are implicated in tau pathology (2020) · cites this paper as [14]
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Citations
Cites
Adjusting batch effects in microarray expression data using empirical Bayes methods
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Self-citationMeta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
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Self-citationChromHMM: automating chromatin-state discovery and characterization
Ernst, J., & Kellis, M. (2012) · Nature Methods · doi:10.1038/nmeth.1906 · Cited by 2,482
Self-citationGenome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease
the European Alzheimer's Disease Initiative Investigators, Lambert, J.-C., Heath, S., Even, G., Campion, D., Sleegers, K., Hiltunen, M., Combarros, O., Zelenika, D., Bullido, M. J., et al. (2009) · Nature Genetics · doi:10.1038/ng.439 · Cited by 2,234
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“We then performed a refinement step similar to that used in “ iSVA” 52 where for each independent component i ( 1 = i =k ) we created a sub-matrix of the beta values populated only by methylation probes that were significantly associated with component i .”
lumi : a pipeline for processing Illumina microarray
Du, P., Kibbe, W. A., & Lin, S. M. (2008) · Bioinformatics · doi:10.1093/bioinformatics/btn224 · Cited by 2,028
Initiative, T. A. D. N., Hollingworth, P., CHARGE consortium, EADI1 consortium, Harold, D., Sims, R., Gerrish, A., Lambert, J.-C., Carrasquillo, M. M., Abraham, R., et al. (2011) · Nature Genetics · doi:10.1038/ng.803 · Cited by 1,997
Naj, A. C., Jun, G., Beecham, G. W., Wang, L.-S., Vardarajan, B. N., Buros, J., Gallins, P. J., Buxbaum, J. D., Jarvik, G. P., Crane, P. K., et al. (2011) · Nature Genetics · doi:10.1038/ng.801 · Cited by 1,901 · cited 1×
“…in the BIN1 locus (beta=4.44, p=9.00×10 −8 ) and cg02308560 in the ABCA7 locus (beta=3.62, p=2.45×10 −12 ) 19-22 . cg22883290, is located 5 kb from the 5’ end of the BIN1 gene and 92 kb from the index SNP, rs744373, that best captures the genetic association to AD in this region ( Figure 2c ) 19 .”
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Integrative analysis of 111 reference human epigenomes
Roadmap Epigenomics Consortium, Kundaje, A., Meuleman, W., Ernst, J., Bilenky, M., Yen, A., Heravi-Moussavi, A., Kheradpour, P., Zhang, Z., Wang, J., et al. (2015) · Nature · doi:10.1038/nature14248 · Cited by 6,368
Self-citationAging and aging-related diseases: from molecular mechanisms to interventions and treatments
Guo, J., Huang, X., Dou, L., Yan, M., Shen, T., Tang, W., & Li, J. (2022) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-022-01251-0 · Cited by 1,976
Editing DNA Methylation in the Mammalian Genome
Liu, X. S., Wu, H., Ji, X., Stelzer, Y., Wu, X., Czauderna, S., Shu, J., Dadon, D., Young, R. A., & Jaenisch, R. (2016) · Cell · doi:10.1016/j.cell.2016.08.056 · Cited by 1,224
“Importantly, these maps have allowed for the identification of differentially methylated regions (DMRs) at base pair resolution during different stages of normal development as well as disease (De Jager et al., 2014; Landau et al., 2014).”
Religious Orders Study and Rush Memory and Aging Project
Bennett, D. A., Buchman, A. S., Boyle, P. A., Barnes, L. L., Wilson, R. S., & Schneider, J. A. (2018) · Journal of Alzheimer's Disease · doi:10.3233/jad-179939 · Cited by 1,260
Self-citationAgeing, neurodegeneration and brain rejuvenation
Wyss-Coray, T. (2016) · Nature · doi:10.1038/nature20411 · Cited by 1,147
Metadata
- Authors
- De Jager, P. L., Srivastava, G., Lunnon, K., Burgess, J., Schalkwyk, L. C., Yu, L., Eaton, M. L., Keenan, B. T., Ernst, J., McCabe, C., Tang, A., Raj, T., Replogle, J., Brodeur, W., Gabriel, S., Chai, H. S., Younkin, C., Younkin, S. G., Zou, F., Szyf, M., Epstein, C. B., Schneider, J. A., Bernstein, B. E., Meissner, A., Ertekin-Taner, N., Chibnik, L. B., Kellis, M., Mill, J., & Bennett, D. A.
- Affiliations
- Broad Institute (US)
- King's College London (GB)
- Mayo Clinic (US)
- Rush University Medical Center (US)
- Brigham and Women's Hospital (US)
- Corresponding author
- Bennett, David A
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-08-17
- Volume
- 17
- Issue
- 9
- Pages
- 1156-1163
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4292795
- OpenAlex
- W2074750860
- Cited by
- 956
- References
- 62
- Citations by year
- 2026: 49 · 2025: 77 · 2024: 74 · 2023: 69 · 2022: 82 · 2021: 94 · 2020: 93 · 2019: 94 · 2018: 93 · 2017: 71 · 2016: 84 · 2015: 59 · 2014: 17
- FWCI
- 31.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Neuroscience (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Open Access at Essex (University of Essex) (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- eScholarship (California Digital Library) (submittedVersion)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Funders
- National Institute on Aging (R01AG017917, P30-AG 10161, K25AG041906, R01AG036039, R01‐AG17917, R01 AG15819, R01AG018023, R01AG036836, U01AG046152, R01-AG18023, AG036039, R01AG036042, R01AG015819, P30AG010161, RC2AG036547, R01AG032990, U01AG046139, RF1AG015819, RF1AG036042, P50AG016574)
- National Human Genome Research Institute (R01HG004037)
- National Institute of Neurological Disorders and Stroke (R01NS080820)
- National Institute of Environmental Health Sciences (U01ES017155)
- National Center for Research Resources (KL2RR024151)
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Keywords
- Alzheimer's disease, DNA methylation, ANK1, BIN1, RHBDF2, ABCA7, differentially methylated regions, gene expression, preclinical Alzheimer's disease, epigenome-wide association study
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Brain, Carrier Proteins, Female, Humans, Male, Middle Aged, Nuclear Proteins, Ankyrins, CpG Islands, DNA Methylation, Genetic Predisposition to Disease, Tumor Suppressor Proteins, Intracellular Signaling Peptides and Proteins, Adaptor Proteins, Signal Transducing, Genome-Wide Association Study, Protein Interaction Maps
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