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Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease

2014; Nature Portfolio; Volume: 17; Issue: 9 Linguagem: Inglês

10.1038/nn.3782

1546-1726

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

Genetic Syndromes and Imprinting

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive neuropathology and cognitive decline. Here the authors describe an epigenome-wide association study (EWAS) of human post-mortem brain samples across multiple independent AD cohorts. They find consistent hypermethylation of the ANK1 gene associated with neuropathology. 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.