Genetic understanding of Parkinson’s disease (PD) is quickly increasing with the emerge of the next-generation sequencing (NGS). Using whole-exome sequencing analyses we recently discovered a polygenic model of inheritance associated with familial and sporadic PD. The aim of this study was to explore the functional role of the most promising genetic variants in a large set of human iPSC-derived dopaminergic neurons.We investigated the presence of alterations at molecular level by an integrated omics (transcriptomic, proteomic and lipidomic) approach in mesencephalic dopaminergic (mdDA) neurons derived from PD patients and controls. Electrophysiological features were assessed by patch–clamp recording.We studied the role of 10 pathogenic variants in 10 PD genes (AIMP2, HMOX2, IMMT, KIF21B, LRRK2, RHOT2, TMEM175, TOMM22, TVP23A, ZSCAN21) in iPSC-derived mdDA neurons. We found that all the genes analysed were expressed at undifferentiated state and during neurons differentiation. Interestingly, we observed that the mutated genes showed a significant different level of expression in patients derived cells with respect to control cells. Preliminary functional data revealed a defect in current recording and in calcium metabolism in patient-derived neurons when compared to healthy subjects. Integrated multi-omics approach identified a wide deregulation of pathways involved in PD pathogenesis including those related to autophagy-lysosomal pathway and mitochondrial metabolism. The analysis of specific molecular signatures associated with PD mutated alleles is still under investigation.In conclusion, our approach extended the knowledge about the interplay between genetics and metabolism in Parkinson’s disease and might pave the way for developing novel therapeutic strategies.