Table 1.
Proteomic and transcriptomic features significantly enriched in ALS-associated genes, which may be useful in gene-specific variant pathogenicity interpretation
| Gene | Significantly enriched feature | Odds ratio | P-value |
|---|---|---|---|
| ANG | β-strand/sheet | 3.57 | 1.05 × 10−3 |
| FUS | Compositional bias | 2.93 | 6.28 × 10−5 |
| PTM site at known variant | 23.19 | 5.12 × 10−4 | |
| Medium expression, all tissues | 2.37 | 1.94 × 10−3 | |
| Medium expression, brain tissues | 2.37 | 1.94 × 10−3 | |
| NEK1 | Helices | 1.80 | 4.81 × 10−5 |
| Buried RSA | 1.93 | 4.39 × 10−5 | |
| High expression, all tissues | 1.98 | 1.52 × 10−4 | |
| OPTN | Helices | 2.76 | 9.52 × 10−4 |
| Medium expression, all tissues | 2.52 | 2.60 × 10−4 | |
| SOD1 | Non-polar to non-polar amino acid change | 57.35 | 2.01 × 10−11 |
| Non-polar to polar amino acid change | 31.49 | 6.04 × 10−10 | |
| β-strand/sheet | 20.78 | 6.97 × 10−14 | |
| Core RSA | 59.34 | 2.11 × 10−13 | |
| Buried RSA | 44.26 | 3.38 × 10−15 | |
| PTM site at known variant | 3.57 | 5.77 × 10−8 | |
| High expression, all tissues | 10.49 | 9.70 × 10−22 | |
| High expression, brain tissues | 10.49 | 9.70 × 10−22 | |
| SQSTM1 | Helices | 1.57 | 6.41 × 10−4 |
| PTM site at known variant | 1.65 | 2.61 × 10−4 | |
| TARDBP | Compositional bias | 27.66 | 1.31 × 10−8 |
| Region of interest | 28.68 | 5.29 × 10−9 | |
| Medium expression, all tissues | 2.63 | 1.96 × 10−3 | |
| Medium expression, brain tissues | 2.63 | 1.96 × 10−3 | |
| VCP | Polar positively charged to polar amino acid change | 13.02 | 2.04 × 10−4 |
| PTM site at known variant | 10.58 | 4.26 × 10−4 |
Results of the combined Cochran–Mantel–Haenszel (CMH) test of the ALS Knowledge Portal and Project MinE ALS sequencing consortium were used to determine significant proteomic and transcriptomic features. An alpha-level of 2.08 × 10−3 was considered significant following Bonferroni correction accounting for the 24 genes analysed. Gene-specific significantly enriched proteomic or transcriptomic features were not observed for the genes: ANXA11, CCNF, CHCHD10, CHMP2B, DAO, DCTN1, DNAJC7, FIG4, HNRNPA1, KIF5A, MATR3, PFN1, TBK1, TUBA4A, UBQLN2 and VAPB. For all gene-based enrichment results see Supplementary Table 8. PTM = post-translational modification; RSA = relative solvent accessible area.