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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.

SUBMITTER: Nho K 

PROVIDER: S-EPMC4387567 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Protective variant for hippocampal atrophy identified by whole exome sequencing.

Nho Kwangsik K   Kim Sungeun S   Risacher Shannon L SL   Shen Li L   Corneveaux Jason J JJ   Swaminathan Shanker S   Lin Hai H   Ramanan Vijay K VK   Liu Yunlong Y   Foroud Tatiana M TM   Inlow Mark H MH   Siniard Ashley L AL   Reiman Rebecca A RA   Aisen Paul S PS   Petersen Ronald C RC   Green Robert C RC   Jack Clifford R CR   Weiner Michael W MW   Baldwin Clinton T CT   Lunetta Kathryn L KL   Farrer Lindsay A LA   Furney Simon J SJ   Lovestone Simon S   Simmons Andrew A   Mecocci Patrizia P   Vellas Bruno B   Tsolaki Magda M   Kloszewska Iwona I   Soininen Hilkka H   McDonald Brenna C BC   Farlow Martin R MR   Ghetti Bernardino B   Huentelman Matthew J MJ   Saykin Andrew J AJ  

Annals of neurology 20150214 3

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 Alzh  ...[more]

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