Extended Data Fig. 5: Deregulated Pathways in iPD between visit 1 and visit 8.

(a) Alterations in DNA damage pathways in iPD and in PD LRRK2 G2019S carriers persist after correction for LEDD and medication type. (b) The same applies to mitochondrial pathways. (c, d) Alterations in DNA damage and mitochondrial pathways in iPD and in PD LRRK2 G2019S carriers persist also after correction for sex. (e-h). Heatmaps of GSEA identified altered pathways common to visit 1 and visit 8 based on (e) Reactome, (f) KEGG, (g) Wikipathways, and (h) GO-BP. Data confirm the findings obtained using the Hallmark database and shared altered pathways are consistent among the analyses. (i) Analysis against the four collections used shows that pathways deregulated exclusively at visit 1 are all down-regulated, consistently with Hallmark analysis, and relate to mitochondrial respiration and DNA repair. (j) Analysis against the four collections used shows that pathways deregulated exclusively at visit 8 in the two experimental groups with sufficient statistical power at this timepoint (i.e. iPD and GBA) are all up-regulated, consistently with Hallmark analysis, and relate to alterations in processes related to oxidant stress, carbohydrate metabolism, and genotoxic stress. In the heatmaps, up- and down-regulated pathways are respectively in red and blue, white boxes indicate unchanged processes; p.adj<0.05. NES: normalized enrichment score. In GSEA, enrichment significance was assessed using a one-sided, permutation-based test on the NES, as implemented in the fgseaMultilevel() function, which employs an adaptive multilevel Monte Carlo algorithm and includes multiple comparison correction to estimate low p-values efficiently.