Whole-exome sequencing and burden analysis identify six novel candidate risk genes and expand the genetic landscape of Parkinson’s disease

Parkinson's Disease (PD) is a complex neurodegenerative disorder with a largely undefined genetic architecture, particularly regarding the role of rare coding variants. We performed a large-scale exome-wide association study to systematically identify rare genetic risk factors for PD. We analyzed whole-exome sequencing (WES) data from 3,602 PD patients and a strictly defined control group of 145,496 individuals of European ancestry from the UK Biobank. We focused on identifying high-confidence protein-truncating variants (PTVs) and used a rigorous gene-based association analysis to find genes significantly associated with PD risk. Our analysis identified PTVs in nine genes that were significantly more frequent in PD cases. These include three previously reported genes for PD/parkinsonism (ATP5F1C, COMMD9, and OPA1) and six novel genes (RGMB, SNX13, MGST2, NMBR, RCBTB1, and JAG1). Following sensitivity analyses, eight genes remained significant. Functional enrichment analysis highlighted pathways related to Notch binding and glutathione transferase activity. This study significantly expands the known genetic landscape of PD by identifying six novel candidate risk genes. Our findings underscore the importance of rare, high-impact PTVs in PD pathogenesis and provide new avenues for mechanistic research and the development of targeted therapeutics.