| Title: | Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease |
| Journal: | Cell Reports |
| Published: | 7 Mar 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40056900/ |
| DOI: | https://doi.org/10.1016/j.celrep.2025.115355 |
Publication 15982
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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 motor deficits, and in vitro assays further suggest a physical interaction between ITSN1 and α-synuclein. These results firmly establish ITSN1 as a PD risk gene with an effect size exceeding previously established loci, implicate vesicular trafficking dysfunction in PD pathogenesis, and potentially open new avenues for therapeutic development.</p>
12 Keywords
- Animals
- Drosophila
- Drosophila Proteins
- Drosophila melanogaster
- Female
- Genetic Predisposition to Disease
- Haploinsufficiency
- Humans
- Male
- Parkinson Disease
- Risk Factors
- alpha-Synuclein
27 Authors
- Thomas P Spargo
- Chloe F Sands
- Isabella R Juan
- Jonathan Mitchell
- Vida Ravanmehr
- Jessica C Butts
- Ruth B De-Paula
- Youngdoo Kim
- Fengyuan Hu
- Quanli Wang
- Dimitrios Vitsios
- Manik Garg
- Lawrence Middleton
- Michal Tyrlik
- Mirko Messa
- Guillermo Del Angel
- Daniel G Calame
- Hiba Saade
- Laurie Robak
- Ben Hollis
- Vishnu A Cuddapah
- Huda Y Zoghbi
- Joshua M Shulman
- Slavé Petrovski
- Ismael Al-Ramahi
- Ioanna Tachmazidou
- Ryan S Dhindsa
2 Applications
| Application ID | Title |
|---|---|
| 26041 | Large-Scale Sequencing in the UK Biobank to Facilitate Gene Discovery, Genome Sciences, and Precision Medicine |
| 68601 | Large-scale whole genome sequencing of the UK Biobank cohort to generate and evaluate therapeutic hypotheses regarding targets, biomarkers and pathways implicated in disease |
Enabling scientific discoveries that improve human health