title: Protective variant for hippocampal atrophy identified by whole exome sequencing.
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.
authors.affiliation: Center for Neuroimaging, Department of Radiology and Imaging Sciences, Indiana University School of Medicine, Indianapolis, IN; Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN.
authors.forename: Kwangsik
authors.initials: K
authors.lastname: Nho
authors.forename: Sungeun
authors.initials: S
authors.lastname: Kim
authors.forename: Shannon L
authors.initials: SL
authors.lastname: Risacher
authors.forename: Li
authors.initials: L
authors.lastname: Shen
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Corneveaux
authors.forename: Shanker
authors.initials: S
authors.lastname: Swaminathan
authors.forename: Hai
authors.initials: H
authors.lastname: Lin
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Ramanan
authors.forename: Yunlong
authors.initials: Y
authors.lastname: Liu
authors.forename: Tatiana M
authors.initials: TM
authors.lastname: Foroud
authors.forename: Mark H
authors.initials: MH
authors.lastname: Inlow
authors.forename: Ashley L
authors.initials: AL
authors.lastname: Siniard
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Reiman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Aisen
authors.forename: Ronald C
authors.initials: RC
authors.lastname: Petersen
authors.forename: Robert C
authors.initials: RC
authors.lastname: Green
authors.forename: Clifford R
authors.initials: CR
authors.lastname: Jack
authors.forename: Michael W
authors.initials: MW
authors.lastname: Weiner
authors.forename: Clinton T
authors.initials: CT
authors.lastname: Baldwin
authors.forename: Kathryn L
authors.initials: KL
authors.lastname: Lunetta
authors.forename: Lindsay A
authors.initials: LA
authors.lastname: Farrer
authors.forename: Simon J
authors.initials: SJ
authors.lastname: Furney
authors.forename: Simon
authors.initials: S
authors.lastname: Lovestone
authors.forename: Andrew
authors.initials: A
authors.lastname: Simmons
authors.forename: Patrizia
authors.initials: P
authors.lastname: Mecocci
authors.forename: Bruno
authors.initials: B
authors.lastname: Vellas
authors.forename: Magda
authors.initials: M
authors.lastname: Tsolaki
authors.forename: Iwona
authors.initials: I
authors.lastname: Kloszewska
authors.forename: Hilkka
authors.initials: H
authors.lastname: Soininen
authors.forename: Brenna C
authors.initials: BC
authors.lastname: McDonald
authors.forename: Martin R
authors.initials: MR
authors.lastname: Farlow
authors.forename: Bernardino
authors.initials: B
authors.lastname: Ghetti
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Huentelman
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Saykin
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000647:Amnesia / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D001284:Atrophy / Q000235:genetics / Q000473:pathology; D060825:Cognitive Dysfunction / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D018450:Disease Progression; D059472:Exome / Q000235:genetics*; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006801:Humans; D008297:Male; D020125:Mutation, Missense; D065840:Protective Factors; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods; D000099229:RE1-Silencing Transcription Factor
chemical_list: D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor