Burden analysis of rare variants (MAF <0.0001) in ALS-associated genes among 1587 patients with ALS and 1866 inhouse controls
| Genes | Rare variants* | P value | Damaging* | P value | Non-damaging* | P value |
| Causative genes | ||||||
| SOD1 | 44, 2 | <1.0E-7 | 43, 1 | <1.0E-7 | 1, 1 | 0.51 |
| FUS | 32, 13 | <1.0E-7 | 19, 3 | <1.0E-6 | 13, 10 | 0.286 |
| VAPB | 5, 6 | 0.99 | 1, 0 | – | 4, 6 | 0.52 |
| TARDBP | 19, 2 | <1.0E-7 | 15, 2 | <1.0E-7 | 4, 0 | <1.0E-7 |
| OPTN | 11, 8 | 0.318 | 6, 0 | <1.0E-7 | 5, 8 | 0.76 |
| VCP | 5, 2 | 0.114 | 4, 1 | 0.076 | 1, 1 | 0.51 |
| UBQLN2 | 7, 6 | 0.442 | 5, 0 | <1.0E-7 | 2, 4 | 0.414 |
| PFN1 | 2, 2 | 0.826 | 1, 1 | 0.51 | 1, 1 | 0.51 |
| HNRNPA1 | 2, 1 | 0.288 | 1, 0 | – | 1, 1 | 0.51 |
| CHCHD10 | 4, 4 | 0.966 | 2, 1 | 0.288 | 2, 3 | 0.702 |
| TBK1 | 13, 7 | 0.06 | 10, 3 | 0.008 | 3, 4 | 0.850 |
| NEK1 | 34, 27 | 0.112 | 17, 6 | 0.002 | 16, 20 | 0.732 |
| ANXA11 | 15, 20 | 0.736 | 7, 3 | 0.202 | 5, 14 | 0.082 |
| KIF5A | 7, 8 | 0.802 | 3, 2 | 0.568 | 4, 6 | 0.52 |
| DNAJC7 | 9, 6 | 0.282 | 3, 1 | 0.146 | 6, 4 | 0.454 |
| Risk or susceptive genes | ||||||
| ALS2 | 25, 35 | 0.408 | 15, 19 | 0.834 | 10, 16 | 0.512 |
| SETX | 41, 39 | 0.348 | 21, 17 | 0.178 | 20, 22 | 0.098 |
| ANG | 2, 7 | 0.104 | 1, 3 | 0.342 | 1, 4 | 0.178 |
| FIG4 | 17, 9 | 0.026 | 9, 5 | 0.088 | 8, 4 | 0.16 |
| SIGMAR1 | 3, 1 | 0.146 | 1, 0 | – | 2, 1 | 0.288 |
| CHMP2B | 4, 2 | 0.376 | 4, 1 | 0.076 | 0, 1 | – |
| SQSTM1 | 10, 8 | 0.360 | 6, 4 | 0.454 | 4, 4 | 0.966 |
| DAO | 9, 12 | 0.642 | 8, 5 | 0.242 | 1, 7 | 0.024 |
| DCTN1 | 7, 21 | 0.022 | 2, 9 | 0.032 | 5, 12 | 0.194 |
| MATR3 | 4, 8 | 0.256 | 2, 3 | 0.702 | 2, 5 | 0.36 |
| TUBA4A | 2, 5 | 0.36 | 1, 5 | 0.09 | 1, 0 | – |
| CCNF | 20, 12 | 0.062 | 9, 5 | 0.088 | 11, 7 | 0.188 |
| TIA1 | 5, 6 | 0.990 | 1, 2 | 0.654 | 4, 4 | 0.966 |
| GLT8D1 | 7, 4 | 0.298 | 3, 2 | 0.568 | 4, 2 | 0.376 |
| CYLD | 5, 7 | 0.796 | 1, 4 | 0.178 | 4, 3 | 0.528 |
| SPG11 | 2, 35 | <1.0E-7 | 2, 16 | <1.0E-7 | 0, 19 | <1.0E-7 |
| NEFH | 19, 28 | 0.362 | 12, 20 | 0.288 | 11, 8 | 0.318 |
| PRPH | 9, 6 | 0.282 | 8, 3 | 0.07 | 1, 3 | 0.342 |
| PNPLA6 | 10, 16 | 0.512 | 3, 4 | 0.85 | 7, 12 | 0.330 |
| ELP3 | 7, 11 | 0.446 | 5, 5 | 0.782 | 2, 6 | 0.140 |
| EWSR1 | 8, 4 | 0.16 | 3, 3 | 0.762 | 5, 1 | 0.048 |
| ERBB4 | 9, 12 | 0.642 | 5, 6 | 0.99 | 4, 6 | 0.52 |
| MAPT | 3, 11 | 0.098 | 2, 3 | 0.702 | 1, 8 | 0.010 |
| GRN | 17, 12 | 0.118 | 7, 3 | 0.202 | 10, 9 | 0.544 |
The p values displayed are from the sequencing kernel association test.
*Represent the number of rare variants, damaging variants and non-damaging variants in 1587 patients with ALS and 1866 inhouse controls. Damaging variants were defined as P/LP variants in the group I genes according to the American College of Medical Genetics and as deleterious variants in the group II genes, all of which are shown in online supplemental table S14 and online supplemental table S15.
ALS, amyotrophic lateral sclerosis; MAF, minor allele frequency; P/LP, pathogenic/likely pathogenic.