Low-frequency genetic variants in GAK enhance Golgi function and protect against Parkinson's disease.

ABSTRACT: Genome-wide association studies (GWAS) have contributed significantly to unraveling the genetic bases of complex diseases such as Parkinson's disease (PD); yet experimental evidence for causation is often elusive. Here, we hypothesized that non-manifesting carriers of a PD-causing mutation in the LRRK2 gene could express genetic modifiers conferring disease protection. Using a pluripotent stem cell-based model, we showed that dopaminergic neurons derived from these individuals were partially protected from the disease in vitro, and that this protective effect is genetically driven. Whole-exome sequencing identified a previously unreported low-frequency variant in cyclin G-associated kinase (GAK) that was associated with a nearly nine-year delay in age at onset among LRRK2 mutation c

SUBMITTER: Calatayud C 

PROVIDER: S-EPMC12363757 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature