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 C Petersen; Robert C Green; Clifford R Jack; Michael W Weiner; Clinton T Baldwin; Kathryn L Lunetta; Lindsay 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; for the Indiana Memory, Aging Study

doi:10.1002/ana.24349

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 C Petersen, Robert C Green, Clifford R 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, for the Indiana Memory, Aging Study

Research output: Contribution to journal › Article › peer-review

45 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 language	English
Journal	Annals of Neurology
DOIs	https://doi.org/10.1002/ana.24349
Publication status	E-pub ahead of print - 2015

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Nho, K., Kim, S., Risacher, S. L., Shen, L., Corneveaux, J. J., Swaminathan, S., Lin, H., Ramanan, V. K., Liu, Y., Foroud, T. M., Inlow, M. H., Siniard, A. L., Reiman, R. A., Aisen, P. S., Petersen, R. C., Green, R. C., Jack, C. R., Weiner, M. W., Baldwin, C. T., ... for the Indiana Memory, Aging Study (2015). Protective variant for hippocampal atrophy identified by whole exome sequencing. Annals of Neurology. Advance online publication. https://doi.org/10.1002/ana.24349

@article{b1cc44ae61f844eca9ae85791f08b6e8,

title = "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.",

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

year = "2015",

doi = "10.1002/ana.24349",

language = "English",

journal = "Annals of Neurology",

issn = "0364-5134",

publisher = "John Wiley and Sons Inc.",

}

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, CR, 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 & for the Indiana Memory, Aging Study 2015, 'Protective variant for hippocampal atrophy identified by whole exome sequencing', Annals of Neurology. https://doi.org/10.1002/ana.24349

TY - JOUR

T1 - Protective variant for hippocampal atrophy identified by whole exome sequencing

AU - Nho, Kwangsik

AU - Kim, Sungeun

AU - Risacher, Shannon L

AU - Shen, Li

AU - Corneveaux, Jason J

AU - Swaminathan, Shanker

AU - Lin, Hai

AU - Ramanan, Vijay K

AU - Liu, Yunlong

AU - Foroud, Tatiana M

AU - Inlow, Mark H

AU - Siniard, Ashley L

AU - Reiman, Rebecca A

AU - Aisen, Paul S

AU - Petersen, Ronald C

AU - Green, Robert C

AU - Jack, Clifford R

AU - Weiner, Michael W

AU - Baldwin, Clinton T

AU - Lunetta, Kathryn L

AU - Farrer, Lindsay A

AU - Furney, Simon J

AU - Lovestone, Simon

AU - Simmons, Andrew

AU - Mecocci, Patrizia

AU - Vellas, Bruno

AU - Tsolaki, Magda

AU - Kloszewska, Iwona

AU - Soininen, Hilkka

AU - McDonald, Brenna C

AU - Farlow, Martin R

AU - Ghetti, Bernardino

AU - Huentelman, Matthew J

AU - Saykin, Andrew J

AU - for the Indiana Memory, Aging Study

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1002/ana.24349

DO - 10.1002/ana.24349

M3 - Article

C2 - 25559091

SN - 0364-5134

JO - Annals of Neurology

JF - Annals of Neurology

ER -

Protective variant for hippocampal atrophy identified by whole exome sequencing

Abstract

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