Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson’s disease
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<sup>-7</sup>; 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<sup>-12</sup>). 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.
Authors
- Laurie Robak (ORCID: https://orcid.org/0000-0001-8279-2504)
- Young-Doo Kim (ORCID: https://orcid.org/0000-0003-0455-5217)
- Thomas P Spargo (ORCID: https://orcid.org/0000-0003-4297-6418)
- Michal Tyrlík (ORCID: https://orcid.org/0000-0002-4928-533X)
- Ismael Al‐Ramahi (ORCID: https://orcid.org/0000-0002-1275-1114)
- Ruth B. De-Paula (ORCID: https://orcid.org/0000-0003-1022-2056)
- Lawrence Middleton (ORCID: https://orcid.org/0009-0002-2789-7244)
- Huda Y. Zoghbi (ORCID: https://orcid.org/0000-0002-0700-3349)
- Hiba Saade
- Fengyuan Hu (ORCID: https://orcid.org/0000-0002-1756-7551)
- Vishnu Anand Cuddapah (ORCID: https://orcid.org/0000-0002-4606-673X)
- Vida Ravanmehr (ORCID: https://orcid.org/0000-0002-3971-1083)
- Daniel G. Calame (ORCID: https://orcid.org/0000-0001-6860-372X)
- Ryan S. Dhindsa (ORCID: https://orcid.org/0000-0002-8965-0813)
- Jonathan Mitchell (ORCID: https://orcid.org/0000-0003-3945-8150)
- Mirko Messa
- Dimitrios Vitsios (ORCID: https://orcid.org/0000-0002-8939-5445)
- Quanli Wang (ORCID: https://orcid.org/0000-0001-7717-4058)
- Guillermo del Angel (ORCID: https://orcid.org/0000-0002-0104-1563)
- Chloe F. Sands
- Ben Hollis
- Manik Garg (ORCID: https://orcid.org/0000-0003-0453-2058)
- Joshua M. Shulman
- Jessica C. Butts (ORCID: https://orcid.org/0000-0003-3193-7165)
- Slavé Petrovski (ORCID: https://orcid.org/0000-0002-1527-961X)
- Isabella R. Juan
- Ioanna Tachmazidou (ORCID: https://orcid.org/0000-0002-1953-2117)
Institutions
- AstraZeneca (United Kingdom) (GB)
- Howard Hughes Medical Institute (US)
- The University of Melbourne (AU)
- Baylor College of Medicine (US)
- AstraZeneca (Australia) (AU)
- AstraZeneca (Singapore) (SG)
- Neurological Research Institute (US)
- AstraZeneca (Sweden) (SE)
- Texas Children's Hospital (US)
- AstraZeneca (United States) (US)
- Genomics (United Kingdom) (GB)
- Austin Health (AU)
- Rice University (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-03-01
- DOI
- https://doi.org/10.1016/j.celrep.2025.115355
- Citations
- 11
- Primary Topic
- RNA regulation and disease
- Type
- article
- Field-Weighted Citation Impact
- 8.87
Funders
- Howard Hughes Medical Institute
- Huffington Foundation
- NIH Office of the Director