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.
N1 - Funding Information:
The authors would like to thank the patients and their family members for their participation in our study. This study was funded by Alzheimer Nederland (WE. 09-2010-06 and WE.15-2014-08) and Internationale Stichting Alzheimer Onderzoek (Grant #11519). L.H.H.M. is supported by Alzheimer Nederland (WE.09-2014-04).
Funding Information:
The authors would like to thank the patients and their family members for their participation in our study. This study was funded by Alzheimer Nederland ( WE. 09-2010-06 and WE.15-2014-08 ) and Internationale Stichting Alzheimer Onderzoek (Grant #11519 ). L.H.H.M. is supported by Alzheimer Nederland ( WE.09-2014-04 ).
Publisher Copyright:
© 2018 The Authors
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
KW - eIF-2 Kinase/genetics
KW - Genetic Association Studies
KW - Alzheimer Disease/genetics
KW - Humans
KW - Middle Aged
KW - Male
KW - Risk
KW - Genetic Variation/genetics
KW - Whole Exome Sequencing
KW - Netherlands
KW - Hippocampus/metabolism
KW - Female
KW - Aged
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
C2 - 30314817
AN - SCOPUS:85054455329
SN - 0197-4580
VL - 73
SP - 229.e11-229.e18
JO - Neurobiology of Aging
JF - Neurobiology of Aging
ER -