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

Abstract

AbstractParkinson’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,GBAandLRRK2, have been previously implicated as risk factors for PD, we identify potential novel associations forB3GNT3, AUNIP, ADH5, TUBA1B, OR1G1, CAPN10, andTREML1. Of these,B3GNT3andTREML1provide new evidence for the role of neuroinflammation in PD. To date, this is the largest analysis of rare genetic variation in PD.