Table 1 The characteristics of genes included in network meta-analysis
Gene | Full name | Location | Category in ALSoD | Proportion of patients with ALS | Common mutations in ALS | Possible pathogenesis | Phenotype | Total HR (95% CI)a |
|---|---|---|---|---|---|---|---|---|
ATXN2 | Ataxin 2 | 12q24.12 | Clinical modifier | <1% in northern European ancestry [88, 89], about 2% in French/French Canadian [90], about 2.5% in Italian [91], < 1% in Turkish [92] and in Chinese [93]. | CAG repeat size ≥ 31 | neurotoxicity caused by prion-like self-assembly and propagation of mutant or misfold protein [1, 94] | Mainly spinal onset | 3.6 (1.1, 12) |
C9orf72 | C9orf72-SMCR8 complex subunit | 9p21.2 | Definitive ALS gene | FALS 33.7%, SALS 5.1% in European, FALS 2.3%, SALS 0.3% in Asian [95]. | GGGGCC hexanucleotide repeat expansion usually > 30, even > 1000 | RNA foci-mediated toxicity; dipeptide repeat protein (DPR)-mediated toxicity; and/or reduced levels of C9orf72 protein [96] | Mainly spinal onset, always with FTD | 1.6 (1.4, 1.9) |
SOD1 | Superoxide dismutase 1 | 21q22.11 | Definitive ALS gene | FALS 14.8%, SALS 1.2% in European. FALS 30.0%, SALS 1.5% in Asian [95]. | A4V, I113T, G41A, A4T, G37R, D90A, D101N, E100G, A140A, D76Y, E21G, H46R, I149T, L106V, L144F, et al | autophagy, mitophagy, and neuroinflammation by mutant or misfold protein aggregates due to decreased SOD1 enzymatic activity [1, 97] | Mainly spinal onset | 0.85 (0.70, 1.0) |
FUS | Fused in sarcoma | 16p11.2 | Definitive ALS gene | FALS 2.8%, SALS 0.3% in European. FALS 6.4%, SALS 0.9% in Asian [95]. | P525L, R495X, R521H, R521C, G504WfsX12, et al | a toxic gain-of-function due to FUS aggregation and/or a loss-of-function resulting from cytoplasmic mis-localization of FUS and subsequent loss of nuclear function [1, 98] | Mainly spinal onset, early-onset | 1.8 (1.1, 2.9) |
TARDBP | TAR DNA binding protein | 1p36.22 | Definitive ALS gene | FALS 4.2%, SALS 0.8% in European. FALS 1.5%, SALS 0.2% in Asian [95]. | A382T, A382T, G294V, G295S, G348C, M337V, et al | neurotoxicity and motor neuron caused by degeneration dysregulation of transposable elements due to TDP-43 loss-of-function [1, 99] | Mainly spinal onset | 0.77 (0.61, 1.0) |
TBK1 | TANK binding kinase 1 | 12q14.2 | Definitive ALS gene | About 2.8% of ALS patients [100] | T79del, G272_T331del, 690-713del, et al | autophagy, mitophagy, and neuroinflammation due to decrease Tbk1’s kinase activity [101] | Mainly spinal onset | 2.4 (0.39, 14.0) |
NEK1 | NIMA related kinase 1 | 4q33 | definitive ALS gene | About 3% of ALS patients [102] | M545T, R261H, et al | impaired function for DNA damage repair [103] | NA | 1.2 (0.49, 2.9) |
UBQLN2 | Ubiquilin 2 | Xp11.21 | Definitive ALS gene | rare [104] | P497H, P506S, T487T, T487I, et al | autophagy, mitophagy, and neuroinflammation by protein blocked protein degradation [105] | Mainly presence with FTD | 0.98 (0.40, 2.5) |
CCNF | Cyclin F | 16p13.3 | Strong evidence | rare [106] | A74T, E528Q, E624K et al | neurotoxicity and motor neuron degeneration by defective protein degradation systems and the pathological accumulation of a protein involved in RNA processing and metabolism [107] | NA | 2.9 (0.19, 45.0) |