期刊
NATURE NEUROSCIENCE
卷 17, 期 9, 页码 1164-1170出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/nn.3782
关键词
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资金
- Alzheimer's Research UK
- US National Institutes of Health [R01 AG036039, AG02219, AG05138, MH064673, R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151, K25 AG041906-01]
- NIHR Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford
- Department of Veterans Affairs VISN3 MIRECC
- Medical Research Council [G1100695, MR/L022656/1] Funding Source: researchfish
- MRC [G1100695, MR/L022656/1] Funding Source: UKRI
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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