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Title | Protective variant for hippocampal atrophy identified by whole exome sequencing. |
Publication Type | Journal Article |
Year of Publication | 2015 |
Authors | Nho K, Kim S, Risacher SL, Shen L, Corneveaux JJ, Swaminathan S, Lin H, Ramanan VK, Liu Y, Foroud TM, Inlow MH, Siniard AL, Reiman RA, Aisen PS, Petersen RC, Green RC, Jack CR, Weiner MW, Baldwin CT, Lunetta KL, Farrer LA, Furney SJ, Lovestone S, Simmons A, Mecocci P, Vellas B, Tsolaki M, Kloszewska I, Soininen H, McDonald BC, Farlow MR, Ghetti B, Huentelman MJ, Saykin AJ |
Corporate Authors | MIRAGE(Multi-Institutional Research on Alzheimer Genetic Epidemiology) Study, AddNeuroMed Consortium, Indiana Memory and Aging Study, Alzheimer's Disease Neuroimaging Initiative |
Journal | Ann Neurol |
Volume | 77 |
Issue | 3 |
Pagination | 547-52 |
Date Published | 03/2015 |
ISSN | 1531-8249 |
Keywords | Aged, Alzheimer Disease, Amnesia, Atrophy, Cognitive Dysfunction, Disease Progression, Exome, Hippocampus, Humans, Male, Mutation, Missense, Protective Factors, Repressor Proteins, Sequence Analysis, DNA |
Abstract | 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. |
DOI | 10.1002/ana.24349 |
Alternate Journal | Ann Neurol |
PubMed ID | 25559091 |
PubMed Central ID | PMC4387567 |
Grant List | AG041232 / AG / NIA NIH HHS / United States R01 AG019771 / AG / NIA NIH HHS / United States R00 LM011384 / LM / NLM NIH HHS / United States P30 AG10133 / AG / NIA NIH HHS / United States R01 AG009029 / AG / NIA NIH HHS / United States P30 AG010133 / AG / NIA NIH HHS / United States U24 AG021886 / AG / NIA NIH HHS / United States U01 AG032984 / AG / NIA NIH HHS / United States U01 AG024904 / AG / NIA NIH HHS / United States P30 AG013846 / AG / NIA NIH HHS / United States R01 AG09029 / AG / NIA NIH HHS / United States RC2 AG036535 / AG / NIA NIH HHS / United States UL1 TR001108 / TR / NCATS NIH HHS / United States IIS-1117335 / / PHS HHS / United States R01 LM011360 / LM / NLM NIH HHS / United States R01 AG19771 / AG / NIA NIH HHS / United States R01 AG041232 / AG / NIA NIH HHS / United States R01 CA101318 / CA / NCI NIH HHS / United States R01 AG25259 / AG / NIA NIH HHS / United States R01 AG025259 / AG / NIA NIH HHS / United States U24 AG21886 / AG / NIA NIH HHS / United States R01NS059873 / NS / NINDS NIH HHS / United States 4R00 LM011384-02 / LM / NLM NIH HHS / United States P30 AG13846 / AG / NIA NIH HHS / United States R01 NS059873 / NS / NINDS NIH HHS / United States |