Figure 5.
Post-translational modification (PTM) features rare missense variants identified across 24 ALS-associated genes. (A) Distribution of PTM features of the residues at which all missense variants were identified. (B) Enrichment analyses were performed using Fisher's exact testing to compare the number of variants carried by individuals with ALS and controls at which PTMs occur in the ALS Knowledge Portal (ALSKP) and Project MinE datasets, followed by a Cochran–Mantel–Haenszel (CMH) test. Significance was measured at an alpha-level of 0.05. (C) Quantile-quantile plots of rare missense variants identified across 24 ALS-associated genes in ALS case-control sequencing datasets, that are located at known post-translational modification sites (PTMVar). Known PTM sites, which were significantly enriched for variants of interest in the individuals with ALS compared to the controls from the two datasets, were further analysed to identify the genes driving the enrichment using Fisher’s exact testing. Enrichment of variants was driven by SOD1 (ALSKP, P = 4.32 × 10−6; Project MinE, P = 3.33 × 10−3; combined analysis, P = 5.77 × 10−8), SQSTM1 (ALSKP, P = 8.13 × 10−5; combined analysis, P = 2.61 × 10−4), FUS (ALSKP, P = 2.43 × 10−3; Project MinE, P = 3.96 × 10−2; combined analysis, P = 5.12 × 10−4) and VCP (ALSKP, P = 4.26 × 10−4; combined analysis, P = 7.13 × 10−4). An alpha-level of 2.08 × 10−3 was considered significant following Bonferroni correction accounting for the 24 genes analysed.