EIF2AK3 variants in Dutch patients with Alzheimer's disease

Journal article (2019)

Authors

Tsz Hang Wong Erasmus MC
S.J. van der Lee Erasmus MC
S.J. van Der Lee Erasmus MC
S.J. Van Der Lee Erasmus MC
More Authors... External organisation
Lieke H.H. Meeter Erasmus MC
Petra Frick German Center for Neurodegenerative Diseases (DZNE)
Shamiram Melhem Erasmus MC
Harro Seelaar Erasmus MC
Mohammad A. Ikram Erasmus MC
M. Arfan Ikram Erasmus MC
M. A. Ikram Erasmus MC
H. Holstege Amsterdam UMC
Henne Holstege Amsterdam UMC
Marc Hulsman Amsterdam UMC, Pattern Recognition and Bioinformatics - EEMCS
M. Hulsman Amsterdam UMC, Pattern Recognition and Bioinformatics - EEMCS
Research Group
Pattern Recognition and Bioinformatics (EEMCS) (TU Delft)
Copyright: © 2019 Tsz Hang Wong, S.J. van der Lee, Jeroen G.J. van Rooij, Lieke H.H. Meeter, Petra Frick, Shamiram Melhem, Harro Seelaar, M. Arfan Ikram, H. Holstege, M. Hulsman, More Authors
DOI: https://doi.org/10.1016/j.neurobiolaging.2018.08.016
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Published Date

2019

Language

English

Faculty

Electrical Engineering, Mathematics and Computer Science

Department

Intelligent Systems

Research Group

Pattern Recognition and Bioinformatics

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.