Analysis of rare Parkinson’s disease variants in millions of people

OBJECTIVE: Although many rare variants have been reportedly associated with Parkinson’s disease (PD), many have not been replicated or have failed to replicate. Here, we conduct a large-scale replication of rare PD variants. METHODS: We assessed a total of 27,590 PD cases, 6,701 PD proxies, and 3,106,080 controls from three data sets: 23andMe, Inc., UK Biobank, and AMP-PD. Based on well-known PD genes, 834 variants of interest were selected from the ClinVar annotated 23andMe dataset. We performed a meta-analysis using summary statistics of all three studies. RESULTS: The meta-analysis resulted in 11 significant variants after Bonferroni correction, including variants in GBA1 and LRRK2. At least 9 previously reported pathogenic or risk variants for PD did not pass Bonferroni correction in this analysis. CONCLUSIONS: Here, we provide the largest rare variant meta-analysis to date, providing thorough information of variants confirmed, newly identified, or rebutted for their association with PD.