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, the BELNEU Consortium, the EU EOD Consortium

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

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 languageEnglish
Pages (from-to)245.e1-245.e7
JournalNeurobiology of Aging
Volume62
DOIs
Publication statusE-pub ahead of print - 2017

Fingerprint

Alzheimer Disease
Phosphotransferases
Mutation
Memory Disorders
Amyotrophic Lateral Sclerosis
Alleles
Frontotemporal Dementia With Motor Neuron Disease

Keywords

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

ASJC Scopus subject areas

  • Neuroscience(all)
  • Ageing
  • Clinical Neurology
  • Developmental Biology
  • Geriatrics and Gerontology

Cite this

Verheijen, J., van der Zee, J., Gijselinck, I., Van den Bossche, T., Dillen, L., Heeman, B., ... the EU EOD Consortium (2017). 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

Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. / Verheijen, Jan; van der Zee, Julie; Gijselinck, Ilse; Van den Bossche, Tobi; Dillen, Lubina; Heeman, Bavo; Gómez-Tortosa, Estrella; Lladó, Albert; Sanchez-Valle, Raquel; Graff, Caroline; Pastor, Pau; Pastor, Maria A.; Benussi, Luisa; Ghidoni, Roberta; Binetti, Giuliano; Clarimon, Jordi; de Mendonça, Alexandre; Gelpi, Ellen; Tsolaki, Magda; Diehl-Schmid, Janine; Nacmias, Benedetta; Almeida, Maria Rosário; Borroni, Barbara; Matej, Radoslav; Ruiz, Agustín; Engelborghs, Sebastiaan; Vandenberghe, Rik; De Deyn, Peter P.; Cruts, Marc; Van Broeckhoven, Christine; Sleegers, Kristel; Goeman, Johan; Nuytten, Dirk; Vandenbulcke, Mathieu; Santens, Patrick; De Bleecker, Jan; Sieben, Anne; Dermaut, Bart; Versijpt, Jan; Michotte, Alex; Deryck, Olivier; Bergmans, Bruno; Willems, Christiana; Ivanoiu, Adrian; Salmon, Eric; Alexopoulos, Panagiotis; Sorbi, Sandro; Bessi, Valentina; Bagnoli, Silvia; Santana, Isabel; the BELNEU Consortium; the EU EOD Consortium.

In: Neurobiology of Aging, Vol. 62, 2017, p. 245.e1-245.e7.

Research output: Contribution to journalArticle

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, the BELNEU Consortium & the EU EOD Consortium 2017, '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
Verheijen J, van der Zee J, Gijselinck I, Van den Bossche T, Dillen L, Heeman B et al. Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. Neurobiology of Aging. 2017;62:245.e1-245.e7. https://doi.org/10.1016/j.neurobiolaging.2017.10.012
Verheijen, Jan ; van der Zee, Julie ; Gijselinck, Ilse ; Van den Bossche, Tobi ; Dillen, Lubina ; Heeman, Bavo ; Gómez-Tortosa, Estrella ; Lladó, Albert ; Sanchez-Valle, Raquel ; Graff, Caroline ; Pastor, Pau ; Pastor, Maria A. ; Benussi, Luisa ; Ghidoni, Roberta ; Binetti, Giuliano ; Clarimon, Jordi ; de Mendonça, Alexandre ; Gelpi, Ellen ; Tsolaki, Magda ; Diehl-Schmid, Janine ; Nacmias, Benedetta ; Almeida, Maria Rosário ; Borroni, Barbara ; Matej, Radoslav ; Ruiz, Agustín ; Engelborghs, Sebastiaan ; Vandenberghe, Rik ; De Deyn, Peter P. ; Cruts, Marc ; Van Broeckhoven, Christine ; Sleegers, Kristel ; Goeman, Johan ; Nuytten, Dirk ; Vandenbulcke, Mathieu ; Santens, Patrick ; De Bleecker, Jan ; Sieben, Anne ; Dermaut, Bart ; Versijpt, Jan ; Michotte, Alex ; Deryck, Olivier ; Bergmans, Bruno ; Willems, Christiana ; Ivanoiu, Adrian ; Salmon, Eric ; Alexopoulos, Panagiotis ; Sorbi, Sandro ; Bessi, Valentina ; Bagnoli, Silvia ; Santana, Isabel ; the BELNEU Consortium ; the EU EOD Consortium. / Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. In: Neurobiology of Aging. 2017 ; Vol. 62. pp. 245.e1-245.e7.
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abstract = "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.",
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AU - Dillen, Lubina

AU - Heeman, Bavo

AU - Gómez-Tortosa, Estrella

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AU - Graff, Caroline

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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

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N2 - 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 - 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.

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KW - Loss-of-function

KW - RNA sequencing

KW - TBK1

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