Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease.

ABSTRACT: Despite its significant heritability, the genetic basis of Parkinson's disease (PD) remains incompletely understood. Here, in analyzing whole-genome sequence data from 3,809 PD cases and 247,101 controls in the UK Biobank, we discover that protein-truncating variants in ITSN1 confer a substantially increased risk of PD (p = 6.1 × 10^-7; odds ratio [95% confidence interval] = 10.5 [5.2, 21.3]). We replicate this association in three independent datasets totaling 8,407 cases and 413,432 controls (combined p = 4.5 × 10^-12). Notably, ITSN1 haploinsufficiency has also been associated with autism spectrum disorder, suggesting variable penetrance/expressivity. In Drosophila, we find that loss of the ITSN1 ortholog Dap160 exacerbates α-synuclein-induced neuronal toxicity and m

SUBMITTER: Spargo TP 

PROVIDER: S-EPMC12124131 | biostudies-literature | 2025 Mar

REPOSITORIES: biostudies-literature