Protective variant for hippocampal atrophy identified by whole exome sequencing

Kwangsik Nho, Sungeun Kim, Shannon L. Risacher, Li Shen, Jason J. Corneveaux, Shanker Swaminathan, Hai Lin, Vijay K. Ramanan, Yunlong Liu, Tatiana M. Foroud, Mark H. Inlow, Ashley L. Siniard, Rebecca A. Reiman, Paul S. Aisen, Ronald Carl Petersen, Robert C. Green, Clifford R Jr. Jack, Michael W. Weiner, Clinton T. Baldwin, Kathryn L. LunettaLindsay A. Farrer, Simon J. Furney, Simon Lovestone, Andrew Simmons, Patrizia Mecocci, Bruno Vellas, Magda Tsolaki, Iwona Kloszewska, Hilkka Soininen, Brenna C. McDonald, Martin R. Farlow, Bernardino Ghetti, Matthew J. Huentelman, Andrew J. Saykin

Research output: Contribution to journalArticle

32 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)547-552
Number of pages6
JournalAnnals of Neurology
Volume77
Issue number3
DOIs
StatePublished - Mar 1 2015

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Exome
Neurogenesis
Neuroimaging
Computer Simulation
Atrophy
Meta-Analysis
Alzheimer Disease
Brain
Therapeutics
Cognitive Dysfunction

ASJC Scopus subject areas

  • Neurology
  • Clinical Neurology

Cite this

Nho, K., Kim, S., Risacher, S. L., Shen, L., Corneveaux, J. J., Swaminathan, S., ... Saykin, A. J. (2015). Protective variant for hippocampal atrophy identified by whole exome sequencing. Annals of Neurology, 77(3), 547-552. https://doi.org/10.1002/ana.24349

Protective variant for hippocampal atrophy identified by whole exome sequencing. / 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 Carl; Green, Robert C.; Jack, Clifford R Jr.; 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.

In: Annals of Neurology, Vol. 77, No. 3, 01.03.2015, p. 547-552.

Research output: Contribution to journalArticle

Nho, K, Kim, S, Risacher, SL, Shen, L, Corneveaux, JJ, Swaminathan, S, Lin, H, Ramanan, VK, Liu, Y, Foroud, TM, Inlow, MH, Siniard, AL, Reiman, RA, Aisen, PS, Petersen, RC, Green, RC, Jack, CRJ, Weiner, MW, Baldwin, CT, Lunetta, KL, Farrer, LA, Furney, SJ, Lovestone, S, Simmons, A, Mecocci, P, Vellas, B, Tsolaki, M, Kloszewska, I, Soininen, H, McDonald, BC, Farlow, MR, Ghetti, B, Huentelman, MJ & Saykin, AJ 2015, 'Protective variant for hippocampal atrophy identified by whole exome sequencing', Annals of Neurology, vol. 77, no. 3, pp. 547-552. https://doi.org/10.1002/ana.24349
Nho K, Kim S, Risacher SL, Shen L, Corneveaux JJ, Swaminathan S et al. Protective variant for hippocampal atrophy identified by whole exome sequencing. Annals of Neurology. 2015 Mar 1;77(3):547-552. https://doi.org/10.1002/ana.24349
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 Carl ; Green, Robert C. ; Jack, Clifford R Jr. ; 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. / Protective variant for hippocampal atrophy identified by whole exome sequencing. In: Annals of Neurology. 2015 ; Vol. 77, No. 3. pp. 547-552.
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