Lunnon Katie, Smith Rebecca, Hannon Eilis, De Jager Philip L, Srivastava Gyan, Volta Manuela, Troakes Claire, Al-Sarraj Safa, Burrage Joe, Macdonald Ruby, Condliffe Daniel, Harries Lorna W, Katsel Pavel, Haroutunian Vahram, Kaminsky Zachary, Joachim Catharine, Powell John, Lovestone Simon, Bennett David A, Schalkwyk Leonard C, Mill Jonathan
University of Exeter Medical School, Exeter University, Exeter, UK.
Institute of Psychiatry, King's College London, London, UK.
Nat Neurosci. 2014 Sep;17(9):1164-70. doi: 10.1038/nn.3782. Epub 2014 Aug 17.
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.
阿尔茨海默病（AD）是一种慢性神经退行性疾病，其特征为进行性神经病理学改变和认知功能衰退。我们使用来自四个独立的人类死后大脑队列的样本，对AD中的甲基化组变异进行了跨组织分析。我们在锚蛋白1（ANK1）基因中鉴定出一个差异甲基化区域，该区域与内嗅皮质（AD表现的主要部位）的神经病理学相关。该区域在另外两个皮质区域（颞上回和前额叶皮质）中被证实存在显著的高甲基化，但在小脑（AD中基本不受神经退行性变影响的区域）或同一受试者生前采集的全血中未出现这种情况。随后在来自三个独立大脑队列的皮质样本中证实了与神经病理学相关的ANK1高甲基化。据我们所知，这项研究是首次采用跨多个组织的序贯复制设计进行的AD全表观基因组关联研究，并突出了这种方法在识别与复杂疾病相关的甲基化组变异方面的作用。
