Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Jan Verheijen; Julie van der Zee; Ilse Gijselinck; Tobi Van den Bossche; Lubina Dillen; Bavo Heeman; Estrella Gómez-Tortosa; Albert Lladó; Raquel Sanchez-Valle; Caroline Graff; Pau Pastor; Maria A. Pastor; Luisa Benussi; Roberta Ghidoni; Giuliano Binetti; Jordi Clarimon; Alexandre de Mendonça; Ellen Gelpi; Magda Tsolaki; Janine Diehl-Schmid; Benedetta Nacmias; Maria Rosário Almeida; Barbara Borroni; Radoslav Matej; Agustín Ruiz; Sebastiaan Engelborghs; Rik Vandenberghe; Peter P. De Deyn; Marc Cruts; Christine Van Broeckhoven; Kristel Sleegers; Johan Goeman; Dirk Nuytten; Mathieu Vandenbulcke; Patrick Santens; Jan De Bleecker; Anne Sieben; Bart Dermaut; Jan Versijpt; Alex Michotte; Olivier Deryck; Bruno Bergmans; Christiana Willems; Adrian Ivanoiu; Eric Salmon; Panagiotis Alexopoulos; Sandro Sorbi; Valentina Bessi; Silvia Bagnoli; Isabel Santana; Frederico Simões do Couto; Madalena Martins; Håkan Thonberg; Laura Fratiglioni; Alessandro Padovani; Zdenek Rohan; Cristina Razquin; Elena Lorenzo; Elena Iglesias; Manuel Seijo-Martínez; Ramon Rene; Jordi Gascon; Jaume Campdelacreu; Maria Koutroumani; Alberto Lleó; Juan Fortea; Rafael Blesa

doi:10.1016/j.neurobiolaging.2017.10.012

Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Jan Verheijen, Julie van der Zee, Ilse Gijselinck, Tobi Van den Bossche, Lubina Dillen, Bavo Heeman, Estrella Gómez-Tortosa, Albert Lladó, Raquel Sanchez-Valle, Caroline Graff, Pau Pastor, Maria A. Pastor, Luisa Benussi, Roberta Ghidoni, Giuliano Binetti, Jordi Clarimon, Alexandre de Mendonça, Ellen Gelpi, Magda Tsolaki, Janine Diehl-SchmidBenedetta Nacmias, Maria Rosário Almeida, Barbara Borroni, Radoslav Matej, Agustín Ruiz, Sebastiaan Engelborghs, Rik Vandenberghe, Peter P. De Deyn, Marc Cruts, Christine Van Broeckhoven, Kristel Sleegers, Johan Goeman, Dirk Nuytten, Mathieu Vandenbulcke, Patrick Santens, Jan De Bleecker, Anne Sieben, Bart Dermaut, Jan Versijpt, Alex Michotte, Olivier Deryck, Bruno Bergmans, Christiana Willems, Adrian Ivanoiu, Eric Salmon, Panagiotis Alexopoulos, Sandro Sorbi, Valentina Bessi, Silvia Bagnoli, Isabel Santana, Frederico Simões do Couto, Madalena Martins, Håkan Thonberg, Laura Fratiglioni, Alessandro Padovani, Zdenek Rohan, Cristina Razquin, Elena Lorenzo, Elena Iglesias, Manuel Seijo-Martínez, Ramon Rene, Jordi Gascon, Jaume Campdelacreu, Maria Koutroumani, Alberto Lleó, Juan Fortea, Rafael Blesa

Department of Medicine

Research output: Contribution to journal › Article › Research › peer-review

15 Citations (Scopus)

Abstract

© 2017 The Author(s) TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.

Original language	English
Pages (from-to)	245.e1-245.e7
Journal	Neurobiology of Aging
Volume	62
DOIs	https://doi.org/10.1016/j.neurobiolaging.2017.10.012
Publication status	Published - 1 Feb 2018

Keywords

Early onset Alzheimer's disease
Frontotemporal dementia
Loss-of-function
RNA sequencing
TBK1

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10.1016/j.neurobiolaging.2017.10.012

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Verheijen, J., van der Zee, J., Gijselinck, I., Van den Bossche, T., Dillen, L., Heeman, B., Gómez-Tortosa, E., Lladó, A., Sanchez-Valle, R., Graff, C., Pastor, P., Pastor, M. A., Benussi, L., Ghidoni, R., Binetti, G., Clarimon, J., de Mendonça, A., Gelpi, E., Tsolaki, M., ... Blesa, R. (2018). Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. Neurobiology of Aging, 62, 245.e1-245.e7. https://doi.org/10.1016/j.neurobiolaging.2017.10.012

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title = "Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort",

abstract = "{\textcopyright} 2017 The Author(s) TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.",

keywords = "Early onset Alzheimer's disease, Frontotemporal dementia, Loss-of-function, RNA sequencing, TBK1",

author = "Jan Verheijen and {van der Zee}, Julie and Ilse Gijselinck and {Van den Bossche}, Tobi and Lubina Dillen and Bavo Heeman and Estrella G{\'o}mez-Tortosa and Albert Llad{\'o} and Raquel Sanchez-Valle and Caroline Graff and Pau Pastor and Pastor, {Maria A.} and Luisa Benussi and Roberta Ghidoni and Giuliano Binetti and Jordi Clarimon and {de Mendon{\c c}a}, Alexandre and Ellen Gelpi and Magda Tsolaki and Janine Diehl-Schmid and Benedetta Nacmias and Almeida, {Maria Ros{\'a}rio} and Barbara Borroni and Radoslav Matej and Agust{\'i}n Ruiz and Sebastiaan Engelborghs and Rik Vandenberghe and {De Deyn}, {Peter P.} and Marc Cruts and {Van Broeckhoven}, Christine and Kristel Sleegers and Johan Goeman and Dirk Nuytten and Mathieu Vandenbulcke and Patrick Santens and {De Bleecker}, Jan and Anne Sieben and Bart Dermaut and Jan Versijpt and Alex Michotte and Olivier Deryck and Bruno Bergmans and Christiana Willems and Adrian Ivanoiu and Eric Salmon and Panagiotis Alexopoulos and Sandro Sorbi and Valentina Bessi and Silvia Bagnoli and Isabel Santana and {Sim{\~o}es do Couto}, Frederico and Madalena Martins and H{\aa}kan Thonberg and Laura Fratiglioni and Alessandro Padovani and Zdenek Rohan and Cristina Razquin and Elena Lorenzo and Elena Iglesias and Manuel Seijo-Mart{\'i}nez and Ramon Rene and Jordi Gascon and Jaume Campdelacreu and Maria Koutroumani and Alberto Lle{\'o} and Juan Fortea and Rafael Blesa",

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month = feb,

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doi = "10.1016/j.neurobiolaging.2017.10.012",

language = "English",

volume = "62",

pages = "245.e1--245.e7",

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Verheijen, J, van der Zee, J, Gijselinck, I, Van den Bossche, T, Dillen, L, Heeman, B, Gómez-Tortosa, E, Lladó, A, Sanchez-Valle, R, Graff, C, Pastor, P, Pastor, MA, Benussi, L, Ghidoni, R, Binetti, G, Clarimon, J, de Mendonça, A, Gelpi, E, Tsolaki, M, Diehl-Schmid, J, Nacmias, B, Almeida, MR, Borroni, B, Matej, R, Ruiz, A, Engelborghs, S, Vandenberghe, R, De Deyn, PP, Cruts, M, Van Broeckhoven, C, Sleegers, K, Goeman, J, Nuytten, D, Vandenbulcke, M, Santens, P, De Bleecker, J, Sieben, A, Dermaut, B, Versijpt, J, Michotte, A, Deryck, O, Bergmans, B, Willems, C, Ivanoiu, A, Salmon, E, Alexopoulos, P, Sorbi, S, Bessi, V, Bagnoli, S, Santana, I, Simões do Couto, F, Martins, M, Thonberg, H, Fratiglioni, L, Padovani, A, Rohan, Z, Razquin, C, Lorenzo, E, Iglesias, E, Seijo-Martínez, M, Rene, R, Gascon, J, Campdelacreu, J, Koutroumani, M, Lleó, A, Fortea, J & Blesa, R 2018, 'Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort', Neurobiology of Aging, vol. 62, pp. 245.e1-245.e7. https://doi.org/10.1016/j.neurobiolaging.2017.10.012

TY - JOUR

T1 - Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

AU - Verheijen, Jan

AU - van der Zee, Julie

AU - Gijselinck, Ilse

AU - Van den Bossche, Tobi

AU - Dillen, Lubina

AU - Heeman, Bavo

AU - Gómez-Tortosa, Estrella

AU - Lladó, Albert

AU - Sanchez-Valle, Raquel

AU - Graff, Caroline

AU - Pastor, Pau

AU - Pastor, Maria A.

AU - Benussi, Luisa

AU - Ghidoni, Roberta

AU - Binetti, Giuliano

AU - Clarimon, Jordi

AU - de Mendonça, Alexandre

AU - Gelpi, Ellen

AU - Tsolaki, Magda

AU - Diehl-Schmid, Janine

AU - Nacmias, Benedetta

AU - Almeida, Maria Rosário

AU - Borroni, Barbara

AU - Matej, Radoslav

AU - Ruiz, Agustín

AU - Engelborghs, Sebastiaan

AU - Vandenberghe, Rik

AU - De Deyn, Peter P.

AU - Cruts, Marc

AU - Van Broeckhoven, Christine

AU - Sleegers, Kristel

AU - Goeman, Johan

AU - Nuytten, Dirk

AU - Vandenbulcke, Mathieu

AU - Santens, Patrick

AU - De Bleecker, Jan

AU - Sieben, Anne

AU - Dermaut, Bart

AU - Versijpt, Jan

AU - Michotte, Alex

AU - Deryck, Olivier

AU - Bergmans, Bruno

AU - Willems, Christiana

AU - Ivanoiu, Adrian

AU - Salmon, Eric

AU - Alexopoulos, Panagiotis

AU - Sorbi, Sandro

AU - Bessi, Valentina

AU - Bagnoli, Silvia

AU - Santana, Isabel

AU - Simões do Couto, Frederico

AU - Martins, Madalena

AU - Thonberg, Håkan

AU - Fratiglioni, Laura

AU - Padovani, Alessandro

AU - Rohan, Zdenek

AU - Razquin, Cristina

AU - Lorenzo, Elena

AU - Iglesias, Elena

AU - Seijo-Martínez, Manuel

AU - Rene, Ramon

AU - Gascon, Jordi

AU - Campdelacreu, Jaume

AU - Koutroumani, Maria

AU - Lleó, Alberto

AU - Fortea, Juan

AU - Blesa, Rafael

PY - 2018/2/1

Y1 - 2018/2/1

N2 - © 2017 The Author(s) TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.

AB - © 2017 The Author(s) TANK-binding kinase 1 (TBK1) loss-of-function (LoF) mutations are known to cause frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS), often combined with memory deficits early in the disease course. We performed targeted resequencing of TBK1 in 1253 early onset Alzheimer's disease (EOAD) patients from 8 European countries to investigate whether pathogenic TBK1 mutations are enriched among patients with clinical diagnosis of EOAD. Variant frequencies were compared against 2117 origin-matched controls. We identified only 1 LoF mutation (p.Thr79del) in a patient clinically diagnosed with Alzheimer's disease and a positive family history of ALS. We did not observe enrichment of rare variants in EOAD patients compared to controls, nor of rare variants affecting NFκB induction. Of 3 common coding variants, rs7486100 showed evidence of association (OR 1.46 [95% CI 1.13–1.9]; p-value 0.01). Homozygous carriers of the risk allele showed reduced expression of TBK1 (p-value 0.03). Our findings are not indicative of a significant role for TBK1 mutations in EOAD. The association between common variants in TBK1, disease risk and reduced TBK1 expression warrants follow-up in FTD/ALS cohorts.

KW - Early onset Alzheimer's disease

KW - Frontotemporal dementia

KW - Loss-of-function

KW - RNA sequencing

KW - TBK1

U2 - 10.1016/j.neurobiolaging.2017.10.012

DO - 10.1016/j.neurobiolaging.2017.10.012

M3 - Article

C2 - 29146049

SN - 0197-4580

VL - 62

SP - 245.e1-245.e7

JO - Neurobiology of Aging

JF - Neurobiology of Aging

ER -

Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort

Abstract

Keywords

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