Study, for the Indiana Memory and Aging
Mayo Clinic
Translational Genomics Research Institute
Citations 1
Protective variant for hippocampal atrophy identified by whole exome sequencing
Kim, Sungeun , Risacher, Shannon L. , Shen, Li , Corneveaux, Jason J., Swaminathan, Shanker , Lin, Hai , Inlow, Mark , Siniard, Ashley L., Reiman, Rebecca, Aisen, Paul, Petersen, Ronald , Jack, 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 , Kłoszewska, Iwona, McDonald, Brenna C. , Farlow, Martin R. , Study, for the Indiana Memory and Aging, Huentelman, Matthew J. , Saykin, Andrew J. , Initiative, for the Alzheimer's Disease Neuroimaging, Nho, Kwangsik T. , Ramanan, Vijay K. , Liu, Yunlong , Foroud, Tatiana , Green, Robert C. , Soininen, Hilkka S. , Ghetti, Bernardino , Study, for the Indiana Memory and Aging, Initiative, for the Alzheimer's Disease Neuroimaging, Jack, Clifford R , Saykin, Andrew J , Shen, Li , Tsolaki, Magda , Mecocci, Patrizia
Annals of Neurology | January 5, 2015 | Volume: 77 | Issue: 3 | Pages: 547-552
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