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.
(2019) Neurobiology of Aging, volume 73, pp. 229.e11 - 229.e18
(Article)
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
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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.
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Keywords: Alzheimer's disease, EIF2AK3, Exome sequencing, PERK, eIF-2 Kinase/genetics, Genetic Association Studies, Alzheimer Disease/genetics, Humans, Middle Aged, Male, Risk, Genetic Variation/genetics, Whole Exome Sequencing, Netherlands, Hippocampus/metabolism, Female, Aged, Clinical Neurology, Geriatrics and Gerontology, Ageing, General Neuroscience, Developmental Biology, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 0197-4580
Publisher: Elsevier Inc.
Note: 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
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