Lunnon, KatieSmith, RebeccaHannon, EilisDe Jager, PhilipSrivastava, GyanVolta, ManuelaTroakes, ClaireAl-Sarraj, SafaBurrage, JoeMacdonald, RubyCondliffe, DanielHarries, Lorna W.Katsel, PavelHaroutunian, VahramKaminsky, ZacharyJoachim, CatharinePowell, JohnLovestone, SimonBennett, David A.Schalkwyk, LeonardMill, Jonathan2015-05-042014Lunnon, K., R. Smith, E. Hannon, P. De Jager, G. Srivastava, M. Volta, C. Troakes, et al. 2014. “Cross-tissue methylomic profiling strongly implicates a role for cortex-specific deregulation of ANK1 in Alzheimer’s disease neuropathology.” Nature neuroscience 17 (9): 1164-1170. doi:10.1038/nn.3782. http://dx.doi.org/10.1038/nn.3782.1097-6256http://nrs.harvard.edu/urn-3:HUL.InstRepos:15034928Alzheimer’s disease (AD) is a chronic neurodegenerative disorder characterized by progressive neuropathology and cognitive decline. We describe a cross-tissue analysis of methylomic variation in AD using samples from three independent human post-mortem brain cohorts. We identify a differentially methylated region in the ankyrin 1 (ANK1) gene that is associated with neuropathology in the entorhinal cortex, a primary site of AD manifestation. This region was confirmed as significantly 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, nor 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 the first epigenome-wide association study (EWAS) 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.en-USJournal Article2015-05-0410.1038/nn.3782