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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1164-1170
Number of pages7
JournalNature Neuroscience
Volume17
Issue number9
DOIs
StatePublished - Sep 1 2014

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Ankyrins
Alzheimer Disease
Temporal Lobe
Entorhinal Cortex
Brain
Prefrontal Cortex
Neurodegenerative Diseases
Cerebellum
Alzheimer disease type 1
Genes
Neuropathology

ASJC Scopus subject areas

  • Neuroscience(all)
  • Medicine(all)

Cite this

Lunnon, K., Smith, R., Hannon, E., De Jager, P. L., Srivastava, G., Volta, M., ... Mill, J. (2014). Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nature Neuroscience, 17(9), 1164-1170. https://doi.org/10.1038/nn.3782

Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. / 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 A; Joachim, Catharine; Powell, John; Lovestone, Simon; Bennett, David A.; Schalkwyk, Leonard C.; Mill, Jonathan.

In: Nature Neuroscience, Vol. 17, No. 9, 01.09.2014, p. 1164-1170.

Research output: Contribution to journalArticle

Lunnon, K, Smith, R, Hannon, E, De Jager, PL, Srivastava, G, Volta, M, Troakes, C, Al-Sarraj, S, Burrage, J, Macdonald, R, Condliffe, D, Harries, LW, Katsel, P, Haroutunian, V, Kaminsky, ZA, Joachim, C, Powell, J, Lovestone, S, Bennett, DA, Schalkwyk, LC & Mill, J 2014, 'Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease', Nature Neuroscience, vol. 17, no. 9, pp. 1164-1170. https://doi.org/10.1038/nn.3782
Lunnon K, Smith R, Hannon E, De Jager PL, Srivastava G, Volta M et al. Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. Nature Neuroscience. 2014 Sep 1;17(9):1164-1170. https://doi.org/10.1038/nn.3782
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 A ; Joachim, Catharine ; Powell, John ; Lovestone, Simon ; Bennett, David A. ; Schalkwyk, Leonard C. ; Mill, Jonathan. / Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease. In: Nature Neuroscience. 2014 ; Vol. 17, No. 9. pp. 1164-1170.
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