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

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.