@article{499c2613001c4596b0414bf081f0d220,
title = "Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease",
abstract = "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.",
author = "Katie Lunnon and Rebecca Smith and Eilis Hannon and {De Jager}, {Philip L.} and Gyan Srivastava and Manuela Volta and Claire Troakes and Safa Al-Sarraj and Joe Burrage and Ruby Macdonald and Daniel Condliffe and Harries, {Lorna W.} and Pavel Katsel and Vahram Haroutunian and Zachary Kaminsky and Catharine Joachim and John Powell and Simon Lovestone and Bennett, {David A.} and Schalkwyk, {Leonard C.} and Jonathan Mill",
note = "Funding Information: We thank C. Sloan for technical support and I. Bodi and A. King for neuropathological diagnosis of cases. We also thank the Oxford Project to Investigate Memory and Ageing (OPTIMA), the National Institute for Health (NIHR) Biomedical Research Unit in Dementia in the South London and Maudsley NHS Foundation Trust (SLaM), Brains for Dementia Research (Alzheimer Brain Bank, UK), and the donors and families who made this research possible. Blood samples from the London cohort were collected as part of the Alzheimer{\textquoteright}s Research UK funded study “Biomarkers of AD Neurodegeneration”. This work was funded by US National Institutes of Health grant R01 AG036039 to J.M. and an Equipment Grant from Alzheimer{\textquoteright}s Research UK. The Oxford Brain Bank is supported in part by the NIHR Oxford Biomedical Research Centre based at Oxford University Hospitals NHS Trust and University of Oxford. Brain banking and neuropathology assessments for the Mount Sinai cohort was supported by US National Institutes of Health grants AG02219, AG05138 and MH064673, and the Department of Veterans Affairs VISN3 MIRECC. Replication work in Boston was supported by US National Institutes of Health grants: R01 AG036042, R01AG036836, R01 AG17917, R01 AG15819, R01 AG032990, R01 AG18023, RC2 AG036547, P30 AG10161, P50 AG016574, U01 ES017155, KL2 RR024151 and K25 AG041906-01. Publisher Copyright: {\textcopyright} 2014 Nature America, Inc. All rights reserved.",
year = "2014",
month = sep,
day = "1",
doi = "10.1038/nn.3782",
language = "English (US)",
volume = "17",
pages = "1164--1170",
journal = "Nature Neuroscience",
issn = "1097-6256",
publisher = "Nature Publishing Group",
number = "9",
}