Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease
Open accessAbstract
Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is characterized by progressive neuropathology and cognitive decline. We performed a cross-tissue analysis of methylomic variation in AD using samples from four independent human post-mortem brain cohorts. We identified a differentially methylated region in the ankyrin 1 (ANK1) gene that was associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as being substantially hypermethylated in two other cortical regions (superior temporal gyrus and prefrontal cortex), but not in the cerebellum, a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem from the same individuals. Neuropathology-associated ANK1 hypermethylation was subsequently confirmed in cortical samples from three independent brain cohorts. This study represents, to the best of our knowledge, the first epigenome-wide association study of AD employing a sequential replication design across multiple tissues and highlights the power of this approach for identifying methylomic variation associated with complex disease.
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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 [19]
The paper’s discussion (page unavailable in our copy) reports extensive differences in DNA methylation across brain regions in AD. It does not establish the broader claim about multiple neurological disorders; this source supports the AD example only. (LLM, conf=0.86)
Experimental — accuracy not yet measuredConsistent with previous studies, 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.
“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 [19]
The paper reports that hypermethylation at two ANK1-associated sites increases with Braak score in cortical regions (main text, page not provided). It does not establish that a majority of AD-associated differences are hypermethylated or that the differences are sex-specific; the Online Methods say sex effects were regressed out. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAlterations 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 [20]
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 [20]
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 [19]
None of the 14 CpGs detected in our interaction analysis was identified in previous large-scale DNA methylation studies.
“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 [19]
Two independent genome-wide studies recently identified a differentially methylated region in the ANK1 gene as associated with the burden of AD pathology.
“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 [198]
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- Authors
- Lunnon, K., Smith, R., Hannon, E., De Jager, P. L., Srivastava, G., Volta, M., Troakes, C., Al-Sarraj, S., Burrage, J., Macdonald, R., Condliffe, D., Harries, L. W., Katsel, P., Haroutunian, V., Kaminsky, Z., Joachim, C., Powell, J., Lovestone, S., Bennett, D. A., Schalkwyk, L. C., & Mill, J.
- Affiliations
- University of Exeter (GB)
- King's College London (GB)
- Broad Institute (US)
- Icahn School of Medicine at Mount Sinai (US)
- Johns Hopkins University (US)
- John Radcliffe Hospital (GB)
- Rush University Medical Center (US)
- Corresponding author
- Mill, Jonathan
- ORCID
- Venue
- Nature Neuroscience
- Published
- 2014-08-17
- Volume
- 17
- Issue
- 9
- Pages
- 1164-1170
- ISSN
- 1097-6256 (ISSN-L)
- 1546-1726
- PMC
- PMC4410018
- OpenAlex
- W1991244004
- Cited by
- 574
- References
- 47
- Citations by year
- 2026: 26 · 2025: 38 · 2024: 43 · 2023: 46 · 2022: 49 · 2021: 56 · 2020: 65 · 2019: 46 · 2018: 56 · 2017: 41 · 2016: 56 · 2015: 37 · 2014: 15
- FWCI
- 20.38
- 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)
- Figshare (submittedVersion)
- Research Portal (King's College London) (submittedVersion, other-oa)
- Open Research Exeter (University of Exeter) (submittedVersion)
- Funders
- Medical Research Council (MR/L022656/1)
- National Institute on Aging (R01AG017917, P30-AG 10161, K25AG041906, R01AG036039, AG-02219, R01‐AG17917, R01 AG15819, R01AG018023, R01AG036836, AG 05138, P50AG005138, R01-AG18023, R01AG036042, R01AG015819, P30AG010161, RC2AG036547, R01AG032990, P01AG002219, RF1AG036042, P50AG016574)
- National Institute of Mental Health (R01MH064673, MH-064673)
- 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 › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Keywords
- Alzheimer's disease, ANK1, DNA methylation, hypermethylation, differentially methylated regions, entorhinal cortex, superior temporal gyrus, prefrontal cortex, cerebellum, epigenome-wide association study, postmortem brain
- MeSH terms
- Aged, Aged, 80 and over, Alzheimer Disease, Cerebral Cortex, Female, Humans, Male, Middle Aged, Temporal Lobe, Prefrontal Cortex, Ankyrins, Entorhinal Cortex, DNA Methylation, Epigenesis, Genetic, Genome-Wide Association Study, Transcriptome
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