Print Email Facebook Twitter EIF2AK3 variants in Dutch patients with Alzheimer's disease Title EIF2AK3 variants in Dutch patients with Alzheimer's disease Author Wong, Tsz Hang (Erasmus MC) van der Lee, S.J. (Erasmus MC) van Rooij, Jeroen G.J. (Erasmus MC) Meeter, Lieke H.H. (Erasmus MC) Frick, Petra (German Center for Neurodegenerative Diseases (DZNE)) Melhem, Shamiram (Erasmus MC) Seelaar, Harro (Erasmus MC) Ikram, M. Arfan (Erasmus MC) Holstege, H. (Amsterdam UMC) Hulsman, M. (TU Delft Pattern Recognition and Bioinformatics; Amsterdam UMC) Date 2019 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. Subject Alzheimer's diseaseEIF2AK3Exome sequencingPERK To reference this document use: http://resolver.tudelft.nl/uuid:0a0571a2-4278-48de-b15b-bd7bc6a38196 DOI https://doi.org/10.1016/j.neurobiolaging.2018.08.016 ISSN 0197-4580 Source Neurobiology of Aging: age-related phenomena, neurodegeneration and neuropathology, 73, 229.e11-229.e18 Part of collection Institutional Repository Document type journal article Rights © 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 Files PDF 1_s2.0_S019745801830304X_main.pdf 1.16 MB Close viewer /islandora/object/uuid:0a0571a2-4278-48de-b15b-bd7bc6a38196/datastream/OBJ/view