The human brainome

network analysis identifies HSPA2 as a novel Alzheimer’s disease target

Vladislav A. Petyuk, Rui Chang, Manuel Ramirez-Restrepo, Noam D. Beckmann, Marc Y.R. Henrion, Paul D. Piehowski, Kuixi Zhu, Sven Wang, Jennifer Clarke, Matthew J. Huentelman, Fang Xie, Victor Andreev, Anzhelika Engel, Toumy Guettoche, Loida Navarro, Philip De Jager, Julie A. Schneider, Christopher M. Morris, Ian G. McKeith, Robert H. Perry & 17 others Simon Lovestone, Randall (Randy) Woltjer, Thomas G. Beach, Lucia I. Sue, Geidy E. Serrano, Andrew P. Lieberman, Roger L. Albin, Isidre Ferrer, Deborah C. Mash, Christine M. Hulette, John F. Ervin, Eric M. Reiman, John A. Hardy, David A. Bennett, Eric Schadt, Richard D. Smith, Amanda J. Myers

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

Original languageEnglish (US)
Pages (from-to)2721-2739
Number of pages19
JournalBrain : a journal of neurology
Volume141
Issue number9
DOIs
StatePublished - Sep 1 2018

Fingerprint

Heat-Shock Proteins
Amyloid
Cell Line
Gene Expression
Proteins
Microtubule-Associated Proteins
Quantitative Trait Loci
Brain
Alleles
RNA
Peptides
DNA
altersolanol A

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

Petyuk, V. A., Chang, R., Ramirez-Restrepo, M., Beckmann, N. D., Henrion, M. Y. R., Piehowski, P. D., ... Myers, A. J. (2018). The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target. Brain : a journal of neurology, 141(9), 2721-2739. https://doi.org/10.1093/brain/awy215

The human brainome : network analysis identifies HSPA2 as a novel Alzheimer’s disease target. / Petyuk, Vladislav A.; Chang, Rui; Ramirez-Restrepo, Manuel; Beckmann, Noam D.; Henrion, Marc Y.R.; Piehowski, Paul D.; Zhu, Kuixi; Wang, Sven; Clarke, Jennifer; Huentelman, Matthew J.; Xie, Fang; Andreev, Victor; Engel, Anzhelika; Guettoche, Toumy; Navarro, Loida; De Jager, Philip; Schneider, Julie A.; Morris, Christopher M.; McKeith, Ian G.; Perry, Robert H.; Lovestone, Simon; Woltjer, Randall (Randy); Beach, Thomas G.; Sue, Lucia I.; Serrano, Geidy E.; Lieberman, Andrew P.; Albin, Roger L.; Ferrer, Isidre; Mash, Deborah C.; Hulette, Christine M.; Ervin, John F.; Reiman, Eric M.; Hardy, John A.; Bennett, David A.; Schadt, Eric; Smith, Richard D.; Myers, Amanda J.

In: Brain : a journal of neurology, Vol. 141, No. 9, 01.09.2018, p. 2721-2739.

Research output: Contribution to journalArticle

Petyuk, VA, Chang, R, Ramirez-Restrepo, M, Beckmann, ND, Henrion, MYR, Piehowski, PD, Zhu, K, Wang, S, Clarke, J, Huentelman, MJ, Xie, F, Andreev, V, Engel, A, Guettoche, T, Navarro, L, De Jager, P, Schneider, JA, Morris, CM, McKeith, IG, Perry, RH, Lovestone, S, Woltjer, RR, Beach, TG, Sue, LI, Serrano, GE, Lieberman, AP, Albin, RL, Ferrer, I, Mash, DC, Hulette, CM, Ervin, JF, Reiman, EM, Hardy, JA, Bennett, DA, Schadt, E, Smith, RD & Myers, AJ 2018, 'The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target', Brain : a journal of neurology, vol. 141, no. 9, pp. 2721-2739. https://doi.org/10.1093/brain/awy215
Petyuk VA, Chang R, Ramirez-Restrepo M, Beckmann ND, Henrion MYR, Piehowski PD et al. The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target. Brain : a journal of neurology. 2018 Sep 1;141(9):2721-2739. https://doi.org/10.1093/brain/awy215
Petyuk, Vladislav A. ; Chang, Rui ; Ramirez-Restrepo, Manuel ; Beckmann, Noam D. ; Henrion, Marc Y.R. ; Piehowski, Paul D. ; Zhu, Kuixi ; Wang, Sven ; Clarke, Jennifer ; Huentelman, Matthew J. ; Xie, Fang ; Andreev, Victor ; Engel, Anzhelika ; Guettoche, Toumy ; Navarro, Loida ; De Jager, Philip ; Schneider, Julie A. ; Morris, Christopher M. ; McKeith, Ian G. ; Perry, Robert H. ; Lovestone, Simon ; Woltjer, Randall (Randy) ; Beach, Thomas G. ; Sue, Lucia I. ; Serrano, Geidy E. ; Lieberman, Andrew P. ; Albin, Roger L. ; Ferrer, Isidre ; Mash, Deborah C. ; Hulette, Christine M. ; Ervin, John F. ; Reiman, Eric M. ; Hardy, John A. ; Bennett, David A. ; Schadt, Eric ; Smith, Richard D. ; Myers, Amanda J. / The human brainome : network analysis identifies HSPA2 as a novel Alzheimer’s disease target. In: Brain : a journal of neurology. 2018 ; Vol. 141, No. 9. pp. 2721-2739.
@article{ecb9502d60074b9783f53a8f769f2a2e,
title = "The human brainome: network analysis identifies HSPA2 as a novel Alzheimer’s disease target",
abstract = "Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.",
author = "Petyuk, {Vladislav A.} and Rui Chang and Manuel Ramirez-Restrepo and Beckmann, {Noam D.} and Henrion, {Marc Y.R.} and Piehowski, {Paul D.} and Kuixi Zhu and Sven Wang and Jennifer Clarke and Huentelman, {Matthew J.} and Fang Xie and Victor Andreev and Anzhelika Engel and Toumy Guettoche and Loida Navarro and {De Jager}, Philip and Schneider, {Julie A.} and Morris, {Christopher M.} and McKeith, {Ian G.} and Perry, {Robert H.} and Simon Lovestone and Woltjer, {Randall (Randy)} and Beach, {Thomas G.} and Sue, {Lucia I.} and Serrano, {Geidy E.} and Lieberman, {Andrew P.} and Albin, {Roger L.} and Isidre Ferrer and Mash, {Deborah C.} and Hulette, {Christine M.} and Ervin, {John F.} and Reiman, {Eric M.} and Hardy, {John A.} and Bennett, {David A.} and Eric Schadt and Smith, {Richard D.} and Myers, {Amanda J.}",
year = "2018",
month = "9",
day = "1",
doi = "10.1093/brain/awy215",
language = "English (US)",
volume = "141",
pages = "2721--2739",
journal = "Brain",
issn = "0006-8950",
publisher = "Oxford University Press",
number = "9",

}

TY - JOUR

T1 - The human brainome

T2 - network analysis identifies HSPA2 as a novel Alzheimer’s disease target

AU - Petyuk, Vladislav A.

AU - Chang, Rui

AU - Ramirez-Restrepo, Manuel

AU - Beckmann, Noam D.

AU - Henrion, Marc Y.R.

AU - Piehowski, Paul D.

AU - Zhu, Kuixi

AU - Wang, Sven

AU - Clarke, Jennifer

AU - Huentelman, Matthew J.

AU - Xie, Fang

AU - Andreev, Victor

AU - Engel, Anzhelika

AU - Guettoche, Toumy

AU - Navarro, Loida

AU - De Jager, Philip

AU - Schneider, Julie A.

AU - Morris, Christopher M.

AU - McKeith, Ian G.

AU - Perry, Robert H.

AU - Lovestone, Simon

AU - Woltjer, Randall (Randy)

AU - Beach, Thomas G.

AU - Sue, Lucia I.

AU - Serrano, Geidy E.

AU - Lieberman, Andrew P.

AU - Albin, Roger L.

AU - Ferrer, Isidre

AU - Mash, Deborah C.

AU - Hulette, Christine M.

AU - Ervin, John F.

AU - Reiman, Eric M.

AU - Hardy, John A.

AU - Bennett, David A.

AU - Schadt, Eric

AU - Smith, Richard D.

AU - Myers, Amanda J.

PY - 2018/9/1

Y1 - 2018/9/1

N2 - Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

AB - Our hypothesis is that changes in gene and protein expression are crucial to the development of late-onset Alzheimer’s disease. Previously we examined how DNA alleles control downstream expression of RNA transcripts and how those relationships are changed in late-onset Alzheimer’s disease. We have now examined how proteins are incorporated into networks in two separate series and evaluated our outputs in two different cell lines. Our pipeline included the following steps: (i) predicting expression quantitative trait loci; (ii) determining differential expression; (iii) analysing networks of transcript and peptide relationships; and (iv) validating effects in two separate cell lines. We performed all our analysis in two separate brain series to validate effects. Our two series included 345 samples in the first set (177 controls, 168 cases; age range 65–105; 58% female; KRONOSII cohort) and 409 samples in the replicate set (153 controls, 141 cases, 115 mild cognitive impairment; age range 66–107; 63% female; RUSH cohort). Our top target is heat shock protein family A member 2 (HSPA2), which was identified as a key driver in our two datasets. HSPA2 was validated in two cell lines, with overexpression driving further elevation of amyloid-β40 and amyloid-β42 levels in APP mutant cells, as well as significant elevation of microtubule associated protein tau and phosphorylated-tau in a modified neuroglioma line. This work further demonstrates that studying changes in gene and protein expression is crucial to understanding late onset disease and further nominates HSPA2 as a specific key regulator of late-onset Alzheimer’s disease processes.10.1093/brain/awy215_video1awy215media15824729224001.

UR - http://www.scopus.com/inward/record.url?scp=85055072616&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85055072616&partnerID=8YFLogxK

U2 - 10.1093/brain/awy215

DO - 10.1093/brain/awy215

M3 - Article

VL - 141

SP - 2721

EP - 2739

JO - Brain

JF - Brain

SN - 0006-8950

IS - 9

ER -