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.