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 Kaminsky; Catharine Joachim; John Powell; Simon Lovestone; David A. Bennett; Leonard C. Schalkwyk; Jonathan Mill

doi:10.1038/nn.3782

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 Kaminsky, Catharine Joachim, John Powell, Simon Lovestone, David A. Bennett, Leonard C. SchalkwykJonathan Mill^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

418 Citations (Scopus)

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 language	English
Pages (from-to)	1164-1170
Number of pages	7
Journal	Nature Neuroscience
Volume	17
Issue number	9
Early online date	17 Aug 2014
DOIs	https://doi.org/10.1038/nn.3782
Publication status	Published - 1 Sept 2014

Keywords

ALLELE-SPECIFIC METHYLATION
BLOOD GENE-EXPRESSION
HUMAN GENOME
SUSCEPTIBILITY
ASSOCIATION
HYPOTHESIS
DIAGNOSIS
LOCI

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/nn.3782

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Lunnon, K., Smith, R., Hannon, E., De Jager, P. L., Srivastava, G., Volta, M., Troakes, C., Al-Sarraj, S., Burrage, J., Macdonald, R., Condliffe, D., Harries, L. W., Katsel, P., Haroutunian, V., Kaminsky, Z., Joachim, C., Powell, J., Lovestone, S., Bennett, D. A., ... 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

@article{5bc16991143d44bea8f2085df8fa5f97,

title = "Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease",

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.",

keywords = "ALLELE-SPECIFIC METHYLATION, BLOOD GENE-EXPRESSION, HUMAN GENOME, SUSCEPTIBILITY, ASSOCIATION, HYPOTHESIS, DIAGNOSIS, LOCI",

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

year = "2014",

month = sep,

day = "1",

doi = "10.1038/nn.3782",

language = "English",

volume = "17",

pages = "1164--1170",

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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, Z, 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

TY - JOUR

T1 - Methylomic profiling implicates cortical deregulation of ANK1 in Alzheimer's disease

AU - Lunnon, Katie

AU - Smith, Rebecca

AU - Hannon, Eilis

AU - De Jager, Philip L.

AU - Srivastava, Gyan

AU - Volta, Manuela

AU - Troakes, Claire

AU - Al-Sarraj, Safa

AU - Burrage, Joe

AU - Macdonald, Ruby

AU - Condliffe, Daniel

AU - Harries, Lorna W.

AU - Katsel, Pavel

AU - Haroutunian, Vahram

AU - Kaminsky, Zachary

AU - Joachim, Catharine

AU - Powell, John

AU - Lovestone, Simon

AU - Bennett, David A.

AU - Schalkwyk, Leonard C.

AU - Mill, Jonathan

PY - 2014/9/1

Y1 - 2014/9/1

N2 - 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.

AB - 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.

KW - ALLELE-SPECIFIC METHYLATION

KW - BLOOD GENE-EXPRESSION

KW - HUMAN GENOME

KW - SUSCEPTIBILITY

KW - ASSOCIATION

KW - HYPOTHESIS

KW - DIAGNOSIS

KW - LOCI

U2 - 10.1038/nn.3782

DO - 10.1038/nn.3782

M3 - Article

SN - 1097-6256

VL - 17

SP - 1164

EP - 1170

JO - Nature Neuroscience

JF - Nature Neuroscience

IS - 9

ER -

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

Abstract

Keywords

UN SDGs

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