This study investigates rare genetic variants associated with Parkinson's disease (PD) using large-scale data from 23andMe, UK Biobank, and AMP-PD, involving over 3 million individuals. The researchers analyzed 27,590 PD cases, 6,701 PD proxies, and 3,106,080 controls. They identified 669 genetic variants, including 834 variants from the ClinVar annotated 23andMe dataset. After a meta-analysis, five variants were found to be statistically significant after Bonferroni correction, including GBA1 and LRRK2 variants. Eight other variants were identified as strong candidates for PD association. The study highlights the importance of rare variants in PD, particularly those with a high penetrance, such as GBA1 and LRRK2. These variants are associated with increased PD risk and have been replicated in previous studies. The research also shows that some variants, while not highly penetrant, may still contribute to PD risk, especially in a recessive inheritance pattern. The study emphasizes the complexity of studying rare variants in large cohorts and the need for larger datasets and more suitable tools to better understand these variants. The findings provide a robust list of PD-associated variants, including five confirmed high-risk variants and eight strong candidate variants. The study also updates risk estimates for these variants, offering more reliable confidence intervals. The results underscore the importance of genetic counseling and the need for further research to better understand the role of rare variants in PD. The study acknowledges limitations, including the need for larger sample sizes and the potential for technical issues in variant selection. Overall, the study contributes valuable insights into the genetic basis of PD and highlights the importance of continued research in this area.This study investigates rare genetic variants associated with Parkinson's disease (PD) using large-scale data from 23andMe, UK Biobank, and AMP-PD, involving over 3 million individuals. The researchers analyzed 27,590 PD cases, 6,701 PD proxies, and 3,106,080 controls. They identified 669 genetic variants, including 834 variants from the ClinVar annotated 23andMe dataset. After a meta-analysis, five variants were found to be statistically significant after Bonferroni correction, including GBA1 and LRRK2 variants. Eight other variants were identified as strong candidates for PD association. The study highlights the importance of rare variants in PD, particularly those with a high penetrance, such as GBA1 and LRRK2. These variants are associated with increased PD risk and have been replicated in previous studies. The research also shows that some variants, while not highly penetrant, may still contribute to PD risk, especially in a recessive inheritance pattern. The study emphasizes the complexity of studying rare variants in large cohorts and the need for larger datasets and more suitable tools to better understand these variants. The findings provide a robust list of PD-associated variants, including five confirmed high-risk variants and eight strong candidate variants. The study also updates risk estimates for these variants, offering more reliable confidence intervals. The results underscore the importance of genetic counseling and the need for further research to better understand the role of rare variants in PD. The study acknowledges limitations, including the need for larger sample sizes and the potential for technical issues in variant selection. Overall, the study contributes valuable insights into the genetic basis of PD and highlights the importance of continued research in this area.