Loss-of-function variants in ITSN1 confer high risk of Parkinson’s disease
Parkinson's disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson's Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.
Authors
- Árni Sturluson (ORCID: https://orcid.org/0000-0002-5074-5727)
- Pálmi V. Jónsson (ORCID: https://orcid.org/0009-0002-7174-2274)
- Hreinn Stefánsson (ORCID: https://orcid.org/0000-0002-9331-6666)
- Guðrún A. Jónsdóttir
- G. Bragi Walters (ORCID: https://orcid.org/0000-0002-5415-6487)
- Kāri Stefánsson (ORCID: https://orcid.org/0000-0003-1676-864X)
- Hannes Helgason
- Thorgeir E. Thorgeirsson (ORCID: https://orcid.org/0000-0002-5149-7040)
- Sigurjón A. Guðjónsson (ORCID: https://orcid.org/0000-0001-9314-7412)
- Ólafur Sveinsson (ORCID: https://orcid.org/0000-0002-4507-2935)
- Daníel F. Guðbjartsson (ORCID: https://orcid.org/0000-0002-5222-9857)
- Gyða Björnsdóttir (ORCID: https://orcid.org/0000-0002-8100-0306)
- Erna V. Ivarsdottir (ORCID: https://orcid.org/0000-0002-2069-0681)
- Anna Bjornsdottir
- Arni F. Gunnarsson (ORCID: https://orcid.org/0000-0001-5940-7487)
- Patrick Sulem (ORCID: https://orcid.org/0000-0001-7123-6123)
- Brynjar Ö. Jensson (ORCID: https://orcid.org/0000-0002-2252-4134)
- Vinicius Tragante (ORCID: https://orcid.org/0000-0002-8223-8957)
- Vala Palmadottir
- Rósa S. Gísladóttir (ORCID: https://orcid.org/0000-0003-0941-1888)
- Ástrós Skúladóttir (ORCID: https://orcid.org/0000-0002-5048-0933)
- Hilma Hólm (ORCID: https://orcid.org/0000-0002-9517-6636)
- Garðar Sveinbjörnsson (ORCID: https://orcid.org/0000-0003-2429-9468)
Institutions
- Reykjavík University (IS)
- deCODE Genetics (Iceland) (IS)
- University of Iceland (IS)
- National University Hospital of Iceland (IS)
Publication Details
- Journal
- npj Parkinson s Disease
- Published
- 2024-08-15
- DOI
- https://doi.org/10.1038/s41531-024-00752-9
- Citations
- 11
- Primary Topic
- Genomics and Rare Diseases
- Type
- article
- Field-Weighted Citation Impact
- 6.05
Funders
- Foundation for the National Institutes of Health
- U.S. Department of Health and Human Services
- Michael J. Fox Foundation for Parkinson's Research
- Pfizer
- GlaxoSmithKline
- Sanofi
- Celgene
- Verily Life Sciences
- National Institutes of Health
- National Institute of Neurological Disorders and Stroke