Background Parkinson’s Disease (PD) and Hutchinson-Gilford Progeria Syndrome (HGPS) are two heterogeneous disorders, which both display molecular and clinical alterations associated with the aging process. However, similarities and differences between molecular changes in these two disorders have not yet been investigated systematically at the level of individual biomolecules and shared molecular network alterations. Methods Here, we perform a comparative meta-analysis and network analysis of human transcriptomics data from case-control studies for both diseases to investigate common susceptibility genes and sub-networks in PD and HGPS. Alzheimer’s disease (AD) and primary melanoma (PM) were included as controls to confirm that the identified overlapping susceptibility genes for PD and HGPS are non-generic. Results We find statistically significant, overlapping genes and cellular processes with significant alterations in both diseases. Interestingly, the majority of these shared affected genes display changes with opposite directionality, indicating that shared susceptible cellular processes undergo different mechanistic changes in PD and HGPS. A complementary regulatory network analysis also reveals that the altered genes in PD and HGPS both contain targets controlled by the upstream regulator CDC5L. Conclusions Overall, our analyses reveal a significant overlap of affected cellular processes and molecular sub-networks in PD and HGPS, including changes in aging-related processes that may reflect key susceptibility factors associated with age-related risk for PD.