EIF2AK3 variants in Dutch patients with Alzheimer's disease

Tsz Hang Wong, Sven J. van der Lee, Jeroen G.J. van Rooij, Lieke H.H. Meeter, Petra Frick, Shamiram Melhem, Harro Seelaar, M. Arfan Ikram, Annemieke J. Rozemuller, Henne Holstege, Marc Hulsman, Andre Uitterlinden, Manuela Neumann, Jeroen J.M. Hoozemans, Cornelia M. van Duijn, Rosa Rademakers, John C. van Swieten

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

Original languageEnglish
Pages (from-to)229.e11-229.e18
JournalNeurobiology of Aging
Volume73
DOIs
Publication statusPublished - 1 Jan 2019

Cite this

Wong, Tsz Hang ; van der Lee, Sven J. ; van Rooij, Jeroen G.J. ; Meeter, Lieke H.H. ; Frick, Petra ; Melhem, Shamiram ; Seelaar, Harro ; Ikram, M. Arfan ; Rozemuller, Annemieke J. ; Holstege, Henne ; Hulsman, Marc ; Uitterlinden, Andre ; Neumann, Manuela ; Hoozemans, Jeroen J.M. ; van Duijn, Cornelia M. ; Rademakers, Rosa ; van Swieten, John C. / EIF2AK3 variants in Dutch patients with Alzheimer's disease. In: Neurobiology of Aging. 2019 ; Vol. 73. pp. 229.e11-229.e18.
@article{ccb7b76b9f3440cd9d1768b7cdb9d625,
title = "EIF2AK3 variants in Dutch patients with Alzheimer's disease",
abstract = "Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95{\%} CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.",
keywords = "Alzheimer's disease, EIF2AK3, Exome sequencing, PERK",
author = "Wong, {Tsz Hang} and {van der Lee}, {Sven J.} and {van Rooij}, {Jeroen G.J.} and Meeter, {Lieke H.H.} and Petra Frick and Shamiram Melhem and Harro Seelaar and Ikram, {M. Arfan} and Rozemuller, {Annemieke J.} and Henne Holstege and Marc Hulsman and Andre Uitterlinden and Manuela Neumann and Hoozemans, {Jeroen J.M.} and {van Duijn}, {Cornelia M.} and Rosa Rademakers and {van Swieten}, {John C.}",
year = "2019",
month = "1",
day = "1",
doi = "10.1016/j.neurobiolaging.2018.08.016",
language = "English",
volume = "73",
pages = "229.e11--229.e18",
journal = "Neurobiology of Aging",
issn = "0197-4580",
publisher = "Elsevier Inc.",

}

Wong, TH, van der Lee, SJ, van Rooij, JGJ, Meeter, LHH, Frick, P, Melhem, S, Seelaar, H, Ikram, MA, Rozemuller, AJ, Holstege, H, Hulsman, M, Uitterlinden, A, Neumann, M, Hoozemans, JJM, van Duijn, CM, Rademakers, R & van Swieten, JC 2019, 'EIF2AK3 variants in Dutch patients with Alzheimer's disease' Neurobiology of Aging, vol. 73, pp. 229.e11-229.e18. https://doi.org/10.1016/j.neurobiolaging.2018.08.016

EIF2AK3 variants in Dutch patients with Alzheimer's disease. / Wong, Tsz Hang; van der Lee, Sven J.; van Rooij, Jeroen G.J.; Meeter, Lieke H.H.; Frick, Petra; Melhem, Shamiram; Seelaar, Harro; Ikram, M. Arfan; Rozemuller, Annemieke J.; Holstege, Henne; Hulsman, Marc; Uitterlinden, Andre; Neumann, Manuela; Hoozemans, Jeroen J.M.; van Duijn, Cornelia M.; Rademakers, Rosa; van Swieten, John C.

In: Neurobiology of Aging, Vol. 73, 01.01.2019, p. 229.e11-229.e18.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - EIF2AK3 variants in Dutch patients with Alzheimer's disease

AU - Wong, Tsz Hang

AU - van der Lee, Sven J.

AU - van Rooij, Jeroen G.J.

AU - Meeter, Lieke H.H.

AU - Frick, Petra

AU - Melhem, Shamiram

AU - Seelaar, Harro

AU - Ikram, M. Arfan

AU - Rozemuller, Annemieke J.

AU - Holstege, Henne

AU - Hulsman, Marc

AU - Uitterlinden, Andre

AU - Neumann, Manuela

AU - Hoozemans, Jeroen J.M.

AU - van Duijn, Cornelia M.

AU - Rademakers, Rosa

AU - van Swieten, John C.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

AB - Next-generation sequencing has contributed to our understanding of the genetics of Alzheimer's disease (AD) and has explained a substantial part of the missing heritability of familial AD. We sequenced 19 exomes from 8 Dutch families with a high AD burden and identified EIF2AK3, encoding for protein kinase RNA-like endoplasmic reticulum kinase (PERK), as a candidate gene. Gene-based burden analysis in a Dutch AD exome cohort containing 547 cases and 1070 controls showed a significant association of EIF2AK3 with AD (OR 1.84 [95% CI 1.07–3.17], p-value 0.03), mainly driven by the variant p.R240H. Genotyping of this variant in an additional cohort from the Rotterdam Study showed a trend toward association with AD (p-value 0.1). Immunohistochemical staining with pPERK and peIF2α of 3 EIF2AK3 AD carriers showed an increase in hippocampal neuronal cells expressing these proteins compared with nondemented controls, but no difference was observed in AD noncarriers. This study suggests that rare variants in EIF2AK3 may be associated with disease risk in AD.

KW - Alzheimer's disease

KW - EIF2AK3

KW - Exome sequencing

KW - PERK

UR - http://www.scopus.com/inward/record.url?scp=85054455329&partnerID=8YFLogxK

U2 - 10.1016/j.neurobiolaging.2018.08.016

DO - 10.1016/j.neurobiolaging.2018.08.016

M3 - Article

VL - 73

SP - 229.e11-229.e18

JO - Neurobiology of Aging

JF - Neurobiology of Aging

SN - 0197-4580

ER -