Protective variant for hippocampal atrophy identified by whole exome sequencing

• Published in: Annals of neurology Vol. 77; no. 3; pp. 547 - 552
• Main 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 Jr, Clifford R., Weiner, Michael W., Baldwin, Clinton T., Lunetta, Kathryn L., Farrer, Lindsay A., Furney, Simon J., Lovestone, Simon, Simmons, Andrew, Mecocci, Patrizia, Vellas, Bruno, Tsolaki, Magda, Kloszewska, Iwona, Soininen, Hilkka, McDonald, Brenna C., Farlow, Martin R., Ghetti, Bernardino, Huentelman, Matthew J., Saykin, Andrew J.
• Format: Journal Article
• Language: English
• Published: United States Blackwell Publishing Ltd 01.03.2015; Wiley Subscription Services, Inc
• Subjects: Aged; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer Disease - physiopathology; Alzheimer's disease; Amnesia - genetics; Amnesia - pathology; Amnesia - physiopathology; Atrophy - genetics; Atrophy - pathology; Cognitive Dysfunction - genetics; Cognitive Dysfunction - pathology; Cognitive Dysfunction - physiopathology; Disease Progression; Exome - genetics; Hippocampus - pathology; Hippocampus - physiopathology; Humans; Male; Medical research; Mutation, Missense; Protective Factors; Repressor Proteins - genetics; Sequence Analysis, DNA - methods
• ISSN: 0364-5134; 1531-8249; 1531-8249
• DOI: 10.1002/ana.24349

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