Protective variant for hippocampal atrophy identified by whole exome sequencing
Copyright policy )Protective variant for hippocampal atrophy identified by whole exome sequencing
We used whole‐exome sequencing to identify variants other than APOE associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An in‐silico predicted missense variant in REST (rs3796529) was found exclusively in subjects with slow hippocampal volume loss and validated using unbiased whole‐brain analysis and meta‐analysis across 5 independent cohorts. REST is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate REST and its functional pathways as protective and illustrate the potential of combining next‐generation sequencing with neuroimaging to discover novel disease mechanisms and potential therapeutic targets. Ann Neurol 2015;77:547–552
- Harvard University United States
- King's College London, University of London
- King's College London United Kingdom
- Mayo Clinic United States
- San Francisco VA Health Care System United States
Male, Aging, MIRAGE (Multi-Institutional Research on Alzheimer Genetic Epidemiology) Study, 1.1 Normal biological development and functioning, Clinical Sciences, Mutation, Missense, 610, Clinical sciences, Neurodegenerative, Alzheimer's Disease, Hippocampus, Alzheimer Disease, 616, Genetics, Acquired Cognitive Impairment, AddNeuroMed Consortium, 2.1 Biological and endogenous factors, Humans, Cognitive Dysfunction, Exome, Aged, Indiana Memory and Aging Study, Neurology & Neurosurgery, Biomedical and Clinical Sciences, Human Genome, Neurosciences, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), DNA, Sequence Analysis, DNA, Protective Factors, Brain Disorders, Repressor Proteins, Neurological, Mutation, Disease Progression, Dementia, Mental health, Amnesia, Missense, Atrophy, Sequence Analysis
Male, Aging, MIRAGE (Multi-Institutional Research on Alzheimer Genetic Epidemiology) Study, 1.1 Normal biological development and functioning, Clinical Sciences, Mutation, Missense, 610, Clinical sciences, Neurodegenerative, Alzheimer's Disease, Hippocampus, Alzheimer Disease, 616, Genetics, Acquired Cognitive Impairment, AddNeuroMed Consortium, 2.1 Biological and endogenous factors, Humans, Cognitive Dysfunction, Exome, Aged, Indiana Memory and Aging Study, Neurology & Neurosurgery, Biomedical and Clinical Sciences, Human Genome, Neurosciences, Alzheimer's Disease Neuroimaging Initiative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), DNA, Sequence Analysis, DNA, Protective Factors, Brain Disorders, Repressor Proteins, Neurological, Mutation, Disease Progression, Dementia, Mental health, Amnesia, Missense, Atrophy, Sequence Analysis
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