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Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis

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Abstract

Recently, mutations in TBK1 (TANK-binding kinase 1) have been reported to be a cause of amyotrophic lateral sclerosis/frontotemporal dementia (ALS/FTD) spectrum, but the relationship between them remains unclear owing to the small sample size and low mutation rate. Therefore, we performed a two-stage meta-analysis to investigate the frequency of TBK1 mutations in ALS/FTD patients and the association between the mutations and risk of ALS/FTD spectrum. In the first stage, 12 studies involving 4173 ALS/FTD patients were included. The frequencies of loss of function (LoF) and missense mutations were 1.0% (95% CI 0.6–1.7%) and 1.8% (95% CI 0.9–3.4%) in ALS/FTD patients respectively. Subgroup analysis suggested a higher prevalence of TBK1 mutations in European patients than that in Asian patients. In the second stage, 7 studies involving 3146 cases and 4856 controls were enrolled. Results showed that TBK1 LoF mutations were associated with a significant increased risk for ALS/FTD spectrum (OR 11.78; 95% CI 4.21–33.00; p < 0.0001), while TBK1 missense mutations were associated with a moderately increased susceptibility for ALS/FTD spectrum (OR 1.62; 95% CI 1.19–2.19; p = 0.002). In conclusion, TBK1 LoF and missense mutations are not frequently found in ALS/FTD patients, and both of them are associated with an increased risk for ALS/FTD spectrum.

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Acknowledgments

The authors thank all those who collaborated in the analysis, interpretation of data, and writing the article. This work was supported by the Natural Science Foundation of Shandong Province under Grant [number ZR2014HM064].

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  1. Department of Neurology, The Affiliated Hospital of Qingdao University, Number 16 Jiangsu Road, Qingdao, Shandong Province, 266003, China

    Rongrong Cui, Miao Tuo, Pengfei Li & Chang Zhou

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Electronic supplementary material

Online resource 1

Quality Assessment of Articles in the first stage (AHRQ). (DOCX 18 kb)

Online resource 2

Quality Assessment of Articles in the second stage (NOS). (DOCX 16 kb)

Online resource 3

a, Begg’s funnel plot of studies reporting TBK1 LoF mutations in ALS/FTD patients. b, Begg’s funnel plot after using trim and fill methods in Fig. S1(a). (GIF 13 kb)

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Online resource 4

a, Begg’s funnel plot of studies reporting TBK1 missense mutations in ALS/FTD patients. b, Begg’s funnel plot after deletion of study by Freishmidt et al. (GIF 13 kb)

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Begg’s funnel plot of TBK1 LoF mutations and risk of ALS/FTD spectrum. (GIF 4 kb)

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Online resource 6

a, Begg’s funnel plot about TBK1 missense mutations and risk of ALS/FTD spectrum. b, Begg’s funnel plot after using trim and fill methods in Fig. S4(b). (GIF 12 kb)

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Cui, R., Tuo, M., Li, P. et al. Association between TBK1 mutations and risk of amyotrophic lateral sclerosis/frontotemporal dementia spectrum: a meta-analysis. Neurol Sci 39, 811–820 (2018). https://doi.org/10.1007/s10072-018-3246-0

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