EIF2AK3 variants in Dutch patients with Alzheimer's disease

Tsz Hang Wong; Sven J. van der Lee; Jeroen G.J. van Rooij; Lieke H.H. Meeter; Petra Frick; Shamiram Melhem; Harro Seelaar; M. Arfan Ikram; Henne Holstege; Marc Hulsman; null More Authors

doi:10.1016/j.neurobiolaging.2018.08.016

EIF2AK3 variants in Dutch patients with Alzheimer's disease

Tsz Hang Wong, Sven J. van der Lee, Jeroen G.J. van Rooij, Lieke H.H. Meeter, Petra Frick, Shamiram Melhem, Harro Seelaar, M. Arfan Ikram, Henne Holstege, Marc Hulsman, More Authors

Pattern Recognition and Bioinformatics

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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.

Original language	English
Pages (from-to)	229.e11-229.e18
Journal	Neurobiology of Aging
Volume	73
DOIs	https://doi.org/10.1016/j.neurobiolaging.2018.08.016
Publication status	Published - 2019

Keywords

Alzheimer's disease
EIF2AK3
Exome sequencing
PERK

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10.1016/j.neurobiolaging.2018.08.016

1-s2.0-S019745801830304X-mainFinal published version, 0.99 MBLicence: CC BY-NC-ND

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title = "EIF2AK3 variants in Dutch patients with Alzheimer's disease",

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.",

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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 - Holstege, Henne

AU - Hulsman, Marc

AU - More Authors, null

PY - 2019

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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.

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EIF2AK3 variants in Dutch patients with Alzheimer's disease

Abstract

Keywords

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