Fig. 2: Genetic FTLD protein co-expression network.

a, A CSF protein co-expression network was built using WGCNA. The genetic FLTD network consisted of 31 protein co-expression modules. Module relatedness is shown in the dendrogram (right). GO analysis was used to identify the principal biology represented by each module. Within genes, module eigenproteins in symptomatic (Sx) and presymptomatic (PreSx) variant carriers were compared against controls. Increased eigenprotein abundance in FTLD is indicated in green, whereas decreased eigenprotein abundance is indicated in blue. Module eigenproteins were correlated with disease outcomes, including CDR + NACC-FTLD, global cognitive slope, CSF NfL and bilateral frontotemporal volumes (red, positive correlation; blue, negative correlation). The cell type nature of each module was assessed by module protein overlap with cell type-specific marker lists of neurons, oligodendrocytes, astrocytes, microglia and endothelia. The asterisks in the left heat map indicate statistical significance after one-way ANOVA with Tukey’s test (two tailed) ***Tukey P < 0.001, **Tukey P < 0.01 and *Tukey P < 0.05. The asterisks in the middle and right heat maps indicate statistical significance after FDR correction: ***FDR P < 0.001, **FDR P < 0.01 and *FDR P < 0.05. The exact P values are reported in Supplementary Table 4. b, Module eigenprotein levels by case status for six of the most strongly FTLD-associated modules. Individual eigenprotein values are plotted in controls (N = 39) and mutation carriers, which were grouped by Sx and PreSx status (C9orf72: 24 PreSx, 23 Sx; GRN: 12 PreSx, 19 Sx; MAPT: 18 PreSx, 19 Sx). Red P values are statistically significant. Differences in module eigenprotein by case status were assessed by one-way ANOVA with Tukey’s test. Gene-specific P values represent the omnibus significance for gene-stratified comparisons versus controls, with significant effects displayed with red text. The box plots represent the median and 25th and 75th percentiles, and box hinges represent the interquartile range of the two middle quartiles within a group. Min and max data points define the extent of whiskers (error bars). C9, C9orf72; CTL, control.