Rare variant screening and burden analysis of PLXNA1 in Parkinson's disease

Background and purpose Recently, p.Glu1121Ter in PLXNA1 was identified as a potential cause of parkinsonism. However, no further replication has been conducted in a wider range of Parkinson's disease (PD) cohorts. We aimed to evaluate the genetic role of PLXNA1 in PD. Methods We systematically analyzed the rare protein-coding variants (minor allele frequency [MAF] < 0.01) in 1080 patients and 1051 healthy controls. Fisher's exact test was used to analyze the associations between each variant and risk of PD, while, at gene level, over-representation of rare variants in patients was examined using the optimized sequence kernel association test (SKAT-O). Results In total, 43 rare variants were identified in PD. No variant was significantly associated with risk of PD. Burden analysis showed enrichment of ultra-rare variants (MAF < 0.001) of PLXNA1 in PD. One patient carried a variant (p.E1121D) in the same amino acid as that in the original study. Both patients showed worsened motor symptoms, and developed dyskinesia during follow-up. Conclusions Our study explored the rare variant of PLXNA1 in PD, and paves the way for future research on the genetic role of PLXNA1 in PD.