Cross-tissue methylomic profiling in Alzheimer’s disease Event

Abstract:

Alzheimer's disease (AD) is a chronic neurodegenerative disorder characterized by progressive neuropathology and cognitive decline. Given the high heritability estimates for AD, considerable effort has focussed on understanding the role of genetic variation in disease aetiology, although it has been recently speculated that epigenetic dysfunction is also likely to be important. Epigenetics refers to the reversible regulation of various genomic functions occurring independently of DNA sequence, with cytosine methylation being the best understood and most stable epigenetic modification modulating the transcription of mammalian genomes. Recent studies have identified global- and gene loci-specific alterations in DNA methylation in AD brain, although to date no epigenome-wide association studies (EWAS) have been published.

In my talk I will describe a systematic, cross-tissue analysis of methylomic variation in AD using samples from three independent post-mortem brain cohorts, which we have recently undertaken in our research group. Most notably, we identify a differentially methylated region (DMR) in the vicinity of the ankrin 1 (ANK1) gene that is strongly associated with neuropathology in the entorhinal cortex (EC), a primary site of AD manifestation in the brain. This region was confirmed as significantly hypermethylated in two other cortical regions (superior temporal gyrus (STG) and prefrontal cortex (PFC)) but not in the cerebellum (CER), a region largely protected from neurodegeneration in AD, or whole blood obtained pre-mortem, from the same individuals. These CpG sites were subsequently found to be significantly hypermethylated in cortical samples from two independent brain cohorts, providing compelling evidence for an association between cortex-specific ANK1 hypermethylation and AD-related neuropathology. This study represents the first epigenome-wide association study (EWAS) of AD employing a sequential replication design across multiple tissues, and highlights the power of this approach for the identification of disease-associated DMRs.

Biography:

Katie is a Lecturer in Epigenetics at the University of Exeter Medical School, with a particular interest in dementia. Katie graduated with a BSc Honours degree in Biochemistry & Pharmacology (1st Class) from the University of Southampton in 2004. It was during this Batchelor's degree that Katie became fascinated by dementia, which naturally led on to her PhD studies in the CNS Inflammation Group at the University of Southampton under the supervision of Professor Hugh Perry. During her PhD she investigated the effect that systemic inflammation has on the brain, particularly in dementia.

In 2008 Katie started a post-doctoral research position in the Department of Old Age Psychiatry in King's College London. In this role she identified peripheral changes that occur in the blood of people with Alzheimer's disease. Subsequently in 2011 Katie moved to the Social, Genetic and Developmental Psychiatry (SGDP) Centre also within King's College London to work in the Psychiatric Epigenetics Group. Here she combined techniques she had previously acquired, with cutting-edge methylomics technology to investigate the role of DNA methylation in late-onset Alzheimer's disease aetiology. This work represented the first high-throughput, genome-wide, cross-tissue methylomic study in Alzheimer's disease.

Katie was appointed as a Lecturer at the University of Exeter Medical School, in June 2013. Here the focus of her research surrounds investigating epigenetic mechanisms in dementia.