The DOI matches its Crossref record; 46 of the 47 references it cites were found in a registry or an index.
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.
Overview
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.
Integrity signals
Registry
Cites
Statistics
Verification
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.
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“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]
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
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
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 [19]
The cited source says what the claim attributes to it.
In the citing paper
“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]
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 [198]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
R: A Language and Environment for Statistical Computing
R Core Team (2000) · doi:10.32614/r.manuals · Cited by 355,893
An integrated encyclopedia of DNA elements in the human genome
The ENCODE Project Consortium (2012) · Nature · doi:10.1038/nature11247 · Cited by 18,072
Neuropathological stageing of Alzheimer-related changes.
Braak, H., & Braak, E. (1991) · Acta Neuropathologica · doi:10.1007/bf00308809 · Cited by 16,123
The Amyloid Hypothesis of Alzheimer’s Disease: Progress and Problems on the Road to Therapeutics
Hardy, J., & Selkoe, D. J. (2002) · Science · doi:10.1126/science.1072994 · Cited by 13,864
Bioconductor: open software development for computational biology and bioinformatics
Gentleman, R. C., Carey, V. J., Bates, D. M., Bolstad, B., Dettling, M., Dudoit, S., Ellis, B., Gautier, L., Ge, Y., Gentry, J., et al. (2004) · Genome biology · doi:10.1186/gb-2004-5-10-r80 · Cited by 12,082
Amyloid oligomers exacerbate tau pathology in a mouse model of tauopathy
Selenica, M.-L. B., Brownlow, M., Jimenez, J. P., Lee, D. C., Pena, G., Dickey, C. A., Gordon, M. N., & Morgan, D. (2013) · Neurodegenerative Diseases · doi:10.1159/000337230 · Cited by 10,359
Alzheimer's disease: the amyloid cascade hypothesis
Hardy, J. A., & Higgins, G. A. (1992) · Science · doi:10.1126/science.1566067 · Cited by 7,484
Meta-Analysis of 74,046 Individuals Identifies 11 New Susceptibility Loci for Alzheimer’s Disease
(EADI), E. A. D. I., Lambert, J.-C., (GERAD), G. A. E. R. I. A. D., Alzheimer's Disease Genetic Consortium (ADGC), (CHARGE), C. F. H. A. A. R. I. G. E., Ibrahim-Verbaas, C. A., Harold, D., Naj, A. C., Sims, R., Bellenguez, C., et al. (2013) · Nature Genetics · doi:10.1038/ng.2802 · Cited by 4,336
Self-citationForecasting the global burden of Alzheimer's disease
Brookmeyer, R., Johnson, E., Ziegler‐Graham, K., & Arrighi, H. M. (2007) · Alzheimer's & Dementia · doi:10.1016/j.jalz.2007.04.381 · Cited by 3,370
The projected effect of risk factor reduction on Alzheimer's disease prevalence
Barnes, D. E., & Yaffe, K. S. (2011) · The Lancet Neurology · doi:10.1016/s1474-4422(11)70072-2 · Cited by 2,846
Chen, Y. A., Lemire, M., Choufani, S., Butcher, D. T., Grafodatskaya, D., Zanke, B. W., Gallinger, S., Hudson, T. J., & Weksberg, R. (2013) · Epigenetics · doi:10.4161/epi.23470 · Cited by 1,547
A data-driven approach to preprocessing Illumina 450K methylation array data
Pidsley, R., Y Wong, C. C., Volta, M., Lunnon, K., Mill, J., & Schalkwyk, L. C. (2013) · BMC Genomics · doi:10.1186/1471-2164-14-293 · Cited by 1,143
Self-citationAlzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
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., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3786 · Cited by 956
Self-citationDavies, M. N., Volta, M., Pidsley, R., Lunnon, K., Dixit, A., Lovestone, S., Coarfa, C., Harris, R. A., Milosavljevic, A., Troakes, C., et al. (2012) · Genome Biology · doi:10.1186/gb-2012-13-6-r43 · Cited by 630
Self-citationNeuropathologic changes in Alzheimer's disease.
Wenk, G. L. (2003) · PubMed · Cited by 554
Comb-p: software for combining, analyzing, grouping and correcting spatially correlated P -values
Pedersen, B. S., Schwartz, D. A., Yang, I. V., & Kechris, K. J. (2012) · Bioinformatics · doi:10.1093/bioinformatics/bts545 · Cited by 485
Dempster, E. L., Pidsley, R., Schalkwyk, L. C., Owens, S., Georgiades, A., Kane, F., Kalidindi, S., Picchioni, M., Kravariti, E., Toulopoulou, T., et al. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr416 · Cited by 460
Self-citationSoranzo, N., Sanna, S., Wheeler, E., Gieger, C., Radke, D., Dupuis, J., Bouatia‐Naji, N., Langenberg, C., Prokopenko, I., Stolerman, E., et al. (2010) · Diabetes · doi:10.2337/db10-0502 · Cited by 448
Guintivano, J., Aryee, M. J., & Kaminsky, Z. A. (2013) · Epigenetics · doi:10.4161/epi.23924 · Cited by 384
Self-citationAllele-specific methylation is prevalent and is contributed by CpG-SNPs in the human genome
Shoemaker, R., Deng, J., Wang, W., & Zhang, K. (2010) · Genome Research · doi:10.1101/gr.104695.109 · Cited by 380
From promises to practical strategies in epigenetic epidemiology
Mill, J. S., & Heijmans, B. T. (2013) · Nature Reviews Genetics · doi:10.1038/nrg3405 · Cited by 356
Self-citationWong, C. C. Y., Meaburn, E. L., Ronald, A., Price, T. S., Jeffries, A. R., Schalkwyk, L. C., Plomin, R., & Mill, J. (2014) · Molecular Psychiatry · doi:10.1038/mp.2013.41 · Cited by 327
Self-citationHaroutunian, V. (1998) · Archives of Neurology · doi:10.1001/archneur.55.9.1185 · Cited by 289
Self-citationMitochondrial Dysfunction and Immune Activation are Detectable in Early Alzheimer's Disease Blood
Lunnon, K., Ibrahim, Z. M., Proitsi, P., Lourdusamy, A., Newhouse, S., Sattlecker, M., Furney, S. J., Saleem, M., Soininen, H. S., Kłoszewska, I., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-111592 · Cited by 145
Self-citationAllele-specific methylation in the human genome: Implications for genetic studies of complex disease
Meaburn, E. L., Schalkwyk, L. C., & Mill, J. (2010) · Epigenetics · doi:10.4161/epi.5.7.12960 · Cited by 132
Self-citationKordeli, E., & Bennett, V. (1991) · The Journal of Cell Biology · doi:10.1083/jcb.114.6.1243 · Cited by 124
A Gene Expression Pattern in Blood for the Early Detection of Alzheimer's Disease
Booij, B. B., Lindahl, T., Wetterberg, P., Skaane, N. V., Sæbø, S., Feten, G., Rye, P. D., Kristiansen, L., Hagen, N., Jensen, M., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101518 · Cited by 114
Boiko, T., Vakulenko, M., Ewers, H., Yap, C. C., Norden, C., & Winckler, B. (2007) · Journal of Neuroscience · doi:10.1523/jneurosci.4302-06.2007 · Cited by 112
Imamura, M., Maeda, S., Yamauchi, T., Hara, K., Yasuda, K., Morizono, T., Takahashi, A., Horikoshi, M., Nakamura, M., Fujita, H., et al. (2012) · Human Molecular Genetics · doi:10.1093/hmg/dds113 · Cited by 112
A Blood Gene Expression Marker of Early Alzheimer's Disease
Lunnon, K., Sattlecker, M., Furney, S. J., Coppola, G., Simmons, A., Proitsi, P., Lupton, M. K., Lourdusamy, A., Johnston, C., Soininen, H. S., et al. (2013) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-121363 · Cited by 104
Self-citationEpigenetics in health and disease: heralding the EWAS era
Murphy, T. M., & Mill, J. S. (2014) · The Lancet · doi:10.1016/s0140-6736(14)60269-5 · Cited by 84
Self-citationLunnon, K., & Mill, J. (2013) · American Journal of Medical Genetics Part B: Neuropsychiatric Genetics · doi:10.1002/ajmg.b.32201 · Cited by 78
Self-citationToward an Alzheimer's disease diagnosis via high‐resolution blood gene expression
Fehlbaum, P., Prado, A. C. J.-L., Pallares, D., Carrière, J., Guihal, C., Soucaille, C., Rouet, F., Drouin, D., Sol, O., Jordan, H. M., et al. (2010) · Alzheimer s & Dementia · doi:10.1016/j.jalz.2009.07.001 · Cited by 76
A Novel Blood Test for the Early Detection of Alzheimer's Disease
Rye, P. D., Booij, B. B., Grave, G., Lindahl, T., Kristiansen, L., Andersen, H., Horndalsveen, P. O., Nygaard, H. A., Naik, M., Hoprekstad, D., et al. (2011) · Journal of Alzheimer s Disease · doi:10.3233/jad-2010-101521 · Cited by 69
Harder, M. N., Ribel‐Madsen, R., Justesen, J. M., Sparsø, T., Galijatovic, E. A. A., Grarup, N., Jørgensen, T., Linneberg, A. R., Hansen, T. F., & Pedersen, O. B. (2013) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2012-4169 · Cited by 68
Fehlbaum, P., on behalf of the EHTAD/002 study group, Sol, O., Désiré, L., Touchon, J., DANTOINE, T. F., Vercelletto, M., Gabelle, A., Jarrige, A.-C., Haddad, R., et al. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120637 · Cited by 64
Laumet, G., Chouraki, V., Grenier-Boley, B., Legry, V., Heath, S., Zelenika, D., Fievet, N., Hannequin, D., Delepine, M., Pasquier, F., et al. (2010) · Journal of Alzheimer's Disease · doi:10.3233/jad-2010-100126 · Cited by 58
Cloning and analysis of Nkx6.3 during CNS and gastrointestinal development
Alanentalo, T., Chatonnet, F., Karlén, M., Sulniute, R., Ericson, J., Andersson, E., & Ahlgren, U. (2005) · Gene Expression Patterns · doi:10.1016/j.modgep.2005.06.012 · Cited by 36
Association of DAPK1 genetic variations with Alzheimer's disease in Han Chinese
Wu, Z., Zhang, W., Yu, J., Zhang, Q., Tian, Y., Lu, R.-C., Yu, N., Zhao-fu, C., & Tan, L. (2010) · Brain Research · doi:10.1016/j.brainres.2010.12.036 · Cited by 23
Soranzo, N., Sanna, S., Wheeler, E., Gieger, C., Radke, D., Dupuis, J., Bouatia‐Naji, N., Langenberg, C., Prokopenko, I., Li, M., et al. (2011) · VU Research Portal · Cited by 21
Expression of Nkx6 Genes in the Hindbrain and Gut of the Developing Mouse
Nelson, S. B., Janiesch, C., & Sander, M. (2005) · Journal of Histochemistry & Cytochemistry · doi:10.1369/jhc.5b6619.2005 · Cited by 19
Corcoy, R. (2011) · Diabetes · doi:10.2337/db10-1368 · Cited by 15
Chapuis, J., Vingtdeux, V., Campagne, F., Davies, P., & Marambaud, P. (2011) · Human Molecular Genetics · doi:10.1093/hmg/ddr085 · Cited by 14
Article Commentary: Alzheimer's Disease, Diagnosis and the Need for Biomarkers
Hooper, C., Lovestone, S., & Sáinz‐Fuertes, R. (2008) · Biomarker Insights · doi:10.4137/bmi.s682 · Cited by 14
Self-citationSearching for biomarkers in neurodegeneration
Lovestone, S. (2010) · Nature Medicine · doi:10.1038/nm1210-1371b · Cited by 9
Self-citationBrain banks: the Oxford experience.
Esiri, M. M. (1993) · PubMed · Cited by 8
Cited by
Sorted by citations
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
The Amyloid-β Pathway in Alzheimer’s Disease
Hampel, H., Hardy, J., Blennow, K., Chen, C., Perry, G., Kim, S. H., Villemagne, V. L., Aisen, P., Vendruscolo, M., Iwatsubo, T., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-021-01249-0 · Cited by 1,952
Ageing, neurodegeneration and brain rejuvenation
Wyss-Coray, T. (2016) · Nature · doi:10.1038/nature20411 · Cited by 1,147
Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci
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., et al. (2014) · Nature Neuroscience · doi:10.1038/nn.3786 · Cited by 956
“To further assess the robustness of our results, we evaluated the 71 significantly associated CpGs in an independent collection of 117 subjects with a different quantitative measure of AD pathology (Braak staging) 24 .”
Self-citationAn epigenetic clock analysis of race/ethnicity, sex, and coronary heart disease
Horvath, S., Gurven, M., Levine, M. E., Trumble, B. C., Kaplan, H. S., Allayee, H., Ritz, B. R., Chen, B. H., Lu, A. T.-H., Rickabaugh, T. M., et al. (2016) · Genome biology · doi:10.1186/s13059-016-1030-0 · Cited by 749
Metadata
- 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
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › 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
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
