EIF2AK3 variants in Dutch patients with Alzheimer's disease

NEUROBIOLOGY OF AGING

卷:73

Article

Wong, Tsz Hang^1,2  van der Lee, Sven J.³  van Rooij, Jeroen G. J.^1,2,4  Meeter, Lieke H. H.^1,2  Frick, Petra⁵  Melhem, Shamiram^1,2  Seelaar, Harro^1,2  Ikram, M. Arfan³  Rozemuller, Annemieke J.⁶  Holstege, Henne^7,8  Hulsman, Marc^7,8,9  Uitterlinden, Andre⁴  Neumann, Manuela^5,10  Hoozemans, Jeroen J. M.⁶  van Duijn, Cornelia M.³  Rademakers, Rosa¹¹  van Swieten, John C.^1,2,7 

[1] Erasmus MC, Alzheimer Ctr, Rotterdam, Netherlands

[2] Erasmus MC, Dept Neurol, Rotterdam, Netherlands

[3] Erasmus MC, Dept Epidemiol, Rotterdam, Netherlands

[4] Erasmus MC, Dept Internal Med, Rotterdam, Netherlands

[5] German Ctr Neurodegenerat Dis, DZNE, Tubingen, Germany

[6] Vrije Univ Amsterdam Med Ctr, Dept Pathol, Amsterdam, Netherlands

[7] Vrije Univ Amsterdam Med Ctr, Alzheimer Ctr, Dept Neurol, Amsterdam, Netherlands

[8] Vrije Univ Amsterdam Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[9] Delft Univ Technol, Delft Bioinformat Lab, Delft, Netherlands

[10] Univ Tubingen, Dept Neuropathol, Tubingen, Germany

[11] Mayo Clin Florida, Dept Neurosci, Jacksonville, FL USA

关键词: Alzheimer's disease;    EIF2AK3;    PERK;    Exome sequencing;   

DOI  :  10.1016/j.neurobiolaging.2018.08.016

来源: Elsevier

【 摘 要 】

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 peIF2 alpha 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. (C) 2018 The Authors. Published by Elsevier Inc.

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