Genetic approach for the discovery of novel therapeutics for Parkinson’s Disease

Abstract

Parkinson’s disease (PD) is a multisystem disorder for which numerous genetic risk loci have been identified, however it is still not clear how these findings connect to the underlying biology or to realistic drug targets. This study brought together 122 genes associated with PD in genomewide association studies (GWAS) and asked three questions: (1) which other diseases are they involved in, (2) which biological pathways they share and (3) whether they are already or a potential drug target for PD. Based on existing genetics studies, these PD associated genes influence multiple traits, commonly recurring in a wide range of neurological, psychiatric, metabolic, oncological and inflammatory conditions. Functional pathways analysis showed that despite this wide range of diseases, the genes share common key processes that affect dopamine, synapses, kinase signaling and calcium balance in the brain. Investigating drug data showed that many of the genes already have clinical stage or approved drugs, mostly for non-PD indications, while others belong to familiar druggable families but currently lack advanced modulators. These results reinforce the idea that PD is a disorder of vulnerable synapses that shares genetic risk with many other disorders and that it's risk genes cluster into a limited number of recurrent pathway networks. By viewing PD GWAS genes through this combined lens of disease links, pathways and druggability, this study highlights both short-term opportunities for rational drug repurposing and a set of promising genes that merit further studies as potential disease modifying targets.