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.
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: Katie
authors.initials: K
authors.lastname: Lunnon
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Rebecca
authors.initials: R
authors.lastname: Smith
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: Eilis
authors.initials: E
authors.lastname: Hannon
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Harvard Medical School, Boston, Massachusetts, USA. [3] Program in Medical and Population Genetics, Broad Institute, Cambridge, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: De Jager
authors.affiliation: 1] Program in Translational NeuroPsychiatric Genomics, Institute for the Neurosciences, Departments of Neurology and Psychiatry, Brigham and Women's Hospital, Boston, Massachusetts, USA. [2] Program in Medical and Population Genetics, Broad Institute, Cambridge, USA.
authors.forename: Gyan
authors.initials: G
authors.lastname: Srivastava
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Manuela
authors.initials: M
authors.lastname: Volta
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Troakes
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Safa
authors.initials: S
authors.lastname: Al-Sarraj
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: Joe
authors.initials: J
authors.lastname: Burrage
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: Ruby
authors.initials: R
authors.lastname: Macdonald
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: Condliffe
authors.affiliation: University of Exeter Medical School, Exeter University, Exeter, UK.
authors.forename: Lorna W
authors.initials: LW
authors.lastname: Harries
authors.affiliation: Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Pavel
authors.initials: P
authors.lastname: Katsel
authors.affiliation: 1] Department of Psychiatry, The Icahn School of Medicine at Mount Sinai, New York, USA. [2] Department of Neuroscience, The Icahn School of Medicine at Mount Sinai, New York, USA. [3] JJ Peters Virginia Medical Center, Bronx, New York, USA.
authors.forename: Vahram
authors.initials: V
authors.lastname: Haroutunian
authors.affiliation: 1] Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. [2] Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Kaminsky
authors.affiliation: Department of Neuropathology, John Radcliffe Hospital, University of Oxford, Oxford, UK.
authors.forename: Catharine
authors.initials: C
authors.lastname: Joachim
authors.affiliation: Institute of Psychiatry, King's College London, London, UK.
authors.forename: John
authors.initials: J
authors.lastname: Powell
authors.affiliation: 1] Institute of Psychiatry, King's College London, London, UK. [2] Department of Psychiatry, Warneford Hospital, University of Oxford, Oxford, UK.
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.affiliation: Rush Alzheimer's Disease Center, Rush University Medical Center, Chicago, Illinois, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Bennett
authors.affiliation: 1] Institute of Psychiatry, King's College London, London, UK. [2].
authors.forename: Leonard C
authors.initials: LC
authors.lastname: Schalkwyk
authors.affiliation: 1] University of Exeter Medical School, Exeter University, Exeter, UK. [2] Institute of Psychiatry, King's College London, London, UK. [3].
authors.forename: Jonathan
authors.initials: J
authors.lastname: Mill
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D017487:Ankyrins / Q000235:genetics*; D002540:Cerebral Cortex / Q000473:pathology / Q000502:physiology*; D019175:DNA Methylation / Q000235:genetics*; D018728:Entorhinal Cortex / Q000473:pathology / Q000502:physiology; D044127:Epigenesis, Genetic / Q000235:genetics; D005260:Female; D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D008875:Middle Aged; D017397:Prefrontal Cortex / Q000473:pathology / Q000502:physiology; D013702:Temporal Lobe / Q000473:pathology / Q000502:physiology; D059467:Transcriptome
chemical_list: C110202:ANK1 protein, human; D017487:Ankyrins