Protective variant for hippocampal atrophy identified by whole exome sequencing. Issue 3 (14th February 2015)

• Record Type: Journal Article
• Authors: Nho, Kwangsik; Kim, Sungeun; Risacher, Shannon L.; Shen, Li; Corneveaux, Jason J.; Swaminathan, Shanker; Lin, Hai; Ramanan, Vijay K.; Liu, Yunlong; Foroud, Tatiana M.; Inlow, Mark H.; Siniard, Ashley L.; Reiman, Rebecca A.; Aisen, Paul S.; Petersen, Ronald C.; Green, Robert C.; Jack, Clifford R.; Weiner, Michael W.; Baldwin, Clinton T.; Lunetta, Kathryn L.; Farrer, Lindsay A.; for the MIRAGE (Multi‐Institutional Research on Alzheimer Genetic Epidemiology) Study; Furney, Simon J.; Lovestone, Simon; Simmons, Andrew; Mecocci, Patrizia; Vellas, Bruno; Tsolaki, Magda; Kloszewska, Iwona; Soininen, Hilkka; for the AddNeuroMed Consortium; McDonald, Brenna C.; Farlow, Martin R.; Ghetti, Bernardino; for the Indiana Memory and Aging Study; Huentelman, Matthew J.; Saykin, Andrew J.; for the Alzheimer's Disease Neuroimaging Initiative;
• Is Part Of: Annals of neurology. Volume 77:Issue 3(2015:Mar.)
• Page Start: 547
• Page End: 552
• Publication Date: 2015-02-14
• Subjects: Neurology -- Periodicals; Pediatric neurology -- Periodicals; Nervous system -- Surgery -- Periodicals; 616.8
• DOI: 10.1002/ana.24349
• Languages: English
• ISSNs: 0364-5134

Abstract

<abstract abstract-type="main"> <title> <x xml:space="preserve">Abstract</x> </title> <p>We used whole‐exome sequencing to identify variants other than <italic>APOE</italic> associated with the rate of hippocampal atrophy in amnestic mild cognitive impairment. An <italic>in‐silico</italic> predicted missense variant in <italic>REST</italic> (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. <italic>REST</italic> is a master regulator of neurogenesis and neuronal differentiation that has not been previously implicated in Alzheimer's disease. These findings nominate <italic>REST</italic> 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</p> </abstract>