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

(2018) NEUROBIOLOGY OF AGING. 62. p.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 NFkB 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, TBK1, Loss-of-function, Frontotemporal dementia, RNA sequencing, AMYOTROPHIC-LATERAL-SCLEROSIS, BINDING KINASE 1, FRONTOTEMPORAL DEMENTIA, BELGIAN COHORT, MUTATIONS, IMMUNITY

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Chicago
Verheijen, Jan, Julie van der Zee, Ilse Gijselinck, Tobi Van den Bossche, Lubina Dillen, Bavo Heeman, Estrella Gómez-Tortosa, et al. 2018. “Common and Rare TBK1 Variants in Early-onset Alzheimer Disease in a European Cohort.” Neurobiology of Aging 62: 245.e1–245.e7.
APA
Verheijen, J., van der Zee, J., Gijselinck, I., Van den Bossche, T., Dillen, L., Heeman, B., Gómez-Tortosa, E., et al. (2018). Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort. NEUROBIOLOGY OF AGING, 62, 245.e1–245.e7.
Vancouver
1.
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. 2018;62:245.e1–245.e7.
MLA
Verheijen, Jan, Julie van der Zee, Ilse Gijselinck, et al. “Common and Rare TBK1 Variants in Early-onset Alzheimer Disease in a European Cohort.” NEUROBIOLOGY OF AGING 62 (2018): 245.e1–245.e7. Print.
@article{8547397,
  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 NFkB 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.},
  author       = {Verheijen, Jan and van der Zee, Julie and Gijselinck, Ilse and Van den Bossche, Tobi and Dillen, Lubina and Heeman, Bavo and G{\'o}mez-Tortosa, Estrella and Llad{\'o}, Albert and Sanchez-Valle, Raquel and Graff, Caroline and Pastor, Pau and Pastor, Maria A and Benussi, Luisa and Ghidoni, Roberta and Binetti, Giuliano and Clarimon, Jordi and de Mendon\c{c}a, Alexandre and Gelpi, Ellen and Tsolaki, Magda and Diehl-Schmid, Janine and Nacmias, Benedetta and Almeida, Maria Ros{\'a}rio and Borroni, Barbara and Matej, Radoslav and Ruiz, Agust{\'i}n and Engelborghs, Sebastiaan and Vandenberghe, Rik and De Deyn, Peter P and Cruts, Marc and Van Broeckhoven, Christine and Sleegers, Kristel and BELNEU Consortium, on behalf of the and Santens, Patrick and De Bleecker, Jan and Sieben, Anne and Dermaut, Bart},
  issn         = {0197-4580},
  journal      = {NEUROBIOLOGY OF AGING},
  keyword      = {Early onset Alzheimer's disease,TBK1,Loss-of-function,Frontotemporal dementia,RNA sequencing,AMYOTROPHIC-LATERAL-SCLEROSIS,BINDING KINASE 1,FRONTOTEMPORAL DEMENTIA,BELGIAN COHORT,MUTATIONS,IMMUNITY},
  language     = {eng},
  pages        = {245.e1--245.e7},
  title        = {Common and rare TBK1 variants in early-onset Alzheimer disease in a European cohort},
  url          = {http://dx.doi.org/10.1016/j.neurobiolaging.2017.10.012},
  volume       = {62},
  year         = {2018},
}

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