Journal Article

Cross-tissue methylomic profiling strongly implicates a role for cortex-specific deregulation of ANK1 in Alzheimer’s disease neuropathology

Volta, Manuela, Powell, John, Bennett, David A., Schalkwyk, Leonard, Burrage, Joe, Condliffe, Daniel, Lunnon, Katie, De Jager, Philip, Katsel, Pavel, Smith, Rebecca, Hannon, Eilis, Mill, Jonathan, Kaminsky, Zachary, Al-Sarraj, Safa, Harries, Lorna W., Srivastava, Gyan, Macdonald, Ruby, Haroutunian, Vahram, Lovestone, Simon, Troakes, Claire, Joachim, Catharine

2014

Overview

Alzheimer’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.