Large-scale Rare Variant Burden Testing in Parkinson’s Disease Identifies Novel Associations with Genes Involved in Neuro-inflammation

Parkinson’s disease (PD) has a large heritable component and genome-wide association studies to date have identified over 90 variants associated with PD, providing deeper insights into the disease biology. However, there have not been large-scale rare variant analyses for PD. To address this gap, we investigated the rare genetic component of PD at minor allele frequencies <1%, using whole genome and whole exome sequencing data from 7,184 PD cases, 6,701 proxy-cases, and 51,650 healthy controls from the Accelerating Medicines Partnership Parkinson’s disease (AMP-PD) initiative, the National Institutes of Health, the UK Biobank, and Genentech. We performed burden tests meta-analyses on protein-altering variants, prioritized based on their predicted functional impact. Our work identified several genes reaching exome-wide significance. While two of these genes, GBA and LRRK2 , have been previously implicated as risk factors for PD, we identify potential novel associations for B3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10 , and TREML1 . Of these, B3GNT3 and TREML1 provide new evidence for the role of neuroinflammation in PD. To date, this is the largest analysis of rare genetic variation in PD.