Systematic rare variant analyses identify RAB32 as a susceptibility gene for familial Parkinson's disease.

ABSTRACT: Despite substantial progress, causal variants are identified only for a minority of familial Parkinson's disease (PD) cases, leaving high-risk pathogenic variants unidentified^1,2. To identify such variants, we uniformly processed exome sequencing data of 2,184 index familial PD cases and 69,775 controls. Exome-wide analyses converged on RAB32 as a novel PD gene identifying c.213C > G/p.S71R as a high-risk variant presenting in ~0.7% of familial PD cases while observed in only 0.004% of controls (odds ratio of 65.5). This variant was confirmed in all cases via Sanger sequencing and segregated with PD in three families. RAB32 encodes a small GTPase known to interact with LRRK2 (refs. ^3,4). Functional analyses showed that RAB32 S71R increases LRRK2 kinase activity, as in

SUBMITTER: Hop PJ 

PROVIDER: S-EPMC11250361 | biostudies-literature | 2024 Jul

REPOSITORIES: biostudies-literature