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 (US) |
|---|---|
| Pages (from-to) | 1164-1170 |
| Number of pages | 7 |
| Journal | Nature Neuroscience |
| Volume | 17 |
| Issue number | 9 |
| DOIs | |
| State | Published - Sep 1 2014 |
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ASJC Scopus subject areas
- Neuroscience(all)
- Medicine(all)
Cite this
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 journal › Article
}
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 A
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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84906716826&partnerID=8YFLogxK
U2 - 10.1038/nn.3782
DO - 10.1038/nn.3782
M3 - Article
C2 - 25129077
AN - SCOPUS:84906716826
VL - 17
SP - 1164
EP - 1170
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 9
ER -