Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease

doi:10.1038/s41531-024-00752-9

. 2024 Aug 15;10(1):140.

doi: 10.1038/s41531-024-00752-9.

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease

Astros Th Skuladottir^{1

2}, Vinicius Tragante³, Gardar Sveinbjornsson³, Hannes Helgason³, Arni Sturluson³, Anna Bjornsdottir⁴, Palmi Jonsson⁵, Vala Palmadottir⁶, Olafur A Sveinsson⁷, Brynjar O Jensson³, Sigurjon A Gudjonsson³, Erna V Ivarsdottir³, Rosa S Gisladottir^{3

8}, Arni F Gunnarsson³, G Bragi Walters³, Gudrun A Jonsdottir³, Thorgeir E Thorgeirsson³, Gyda Bjornsdottir³, Hilma Holm³, Daniel F Gudbjartsson^{3

9}, Patrick Sulem³, Hreinn Stefansson³, Kari Stefansson^{10

11}

Affiliations

¹ deCODE genetics/Amgen Inc., Reykjavik, Iceland. astros.skuladottir@decode.is.
² Faculty of Medicine, University of Iceland, Reykjavik, Iceland. astros.skuladottir@decode.is.
³ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
⁴ Heilsuklasinn Clinic, Reykjavik, Iceland.
⁵ Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
⁶ Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸ Faculty of Icelandic and Comparative Cultural Studies, University of Iceland, Reykjavik, Iceland.
⁹ Faculty of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
¹⁰ deCODE genetics/Amgen Inc., Reykjavik, Iceland. kstefans@decode.is.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.

PMID: 39147844
PMCID: PMC11327306
DOI: 10.1038/s41531-024-00752-9

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease

Astros Th Skuladottir et al. NPJ Parkinsons Dis. 2024.

. 2024 Aug 15;10(1):140.

doi: 10.1038/s41531-024-00752-9.

Authors

Affiliations

¹ deCODE genetics/Amgen Inc., Reykjavik, Iceland. astros.skuladottir@decode.is.
² Faculty of Medicine, University of Iceland, Reykjavik, Iceland. astros.skuladottir@decode.is.
³ deCODE genetics/Amgen Inc., Reykjavik, Iceland.
⁴ Heilsuklasinn Clinic, Reykjavik, Iceland.
⁵ Department of Geriatric Medicine, Landspitali University Hospital, Reykjavik, Iceland.
⁶ Department of Internal Medicine, Landspitali University Hospital, Reykjavik, Iceland.
⁷ Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
⁸ Faculty of Icelandic and Comparative Cultural Studies, University of Iceland, Reykjavik, Iceland.
⁹ Faculty of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
¹⁰ deCODE genetics/Amgen Inc., Reykjavik, Iceland. kstefans@decode.is.
¹¹ Faculty of Medicine, University of Iceland, Reykjavik, Iceland. kstefans@decode.is.

PMID: 39147844
PMCID: PMC11327306
DOI: 10.1038/s41531-024-00752-9

Abstract

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.

PubMed Disclaimer

Conflict of interest statement

A.T.S., V.T., G.S., Ha.H., A.S., B.O.J., S.A.G., E.V.I., R.S.G., A.F.G., G.B.W., G.A.J., T.E.T., G.B., Hi.H., D.F.G., P.S., H.S., and K.S. are employees of deCODE genetics/Amgen Inc. The remaining authors declare no competing interests.

Figures

**Fig. 1**
Overview of study design and summary of results.

See this image and copyright information in PMC

Cited by

Haploinsufficiency of ITSN1 is associated with a substantial increased risk of Parkinson's disease.
Spargo TP, Sands CF, Juan IR, Mitchell J, Ravanmehr V, Butts JC, De-Paula RB, Kim Y, Hu F, Wang Q, Vitsios D, Garg M, Middleton L, Tyrlik M, Messa M, Del Angel G, Calame DG, Saade H, Robak L, Hollis B, Cuddapah VA, Zoghbi HY, Shulman JM, Petrovski S, Al-Ramahi I, Tachmazidou I, Dhindsa RS. Spargo TP, et al. Cell Rep. 2025 Mar 25;44(3):115355. doi: 10.1016/j.celrep.2025.115355. Epub 2025 Mar 7. Cell Rep. 2025. PMID: 40056900 Free PMC article.
Novel Parkinson's Disease Genetic Risk Factors Within and Across European Populations.
Leonard HL; Global Parkinson’s Genetics Program (GP2). Leonard HL, et al. medRxiv [Preprint]. 2025 Mar 17:2025.03.14.24319455. doi: 10.1101/2025.03.14.24319455. medRxiv. 2025. PMID: 40166558 Free PMC article. Preprint.
CircITSN1/EIF4A3/Itsn1 axis mediates postoperative cognitive dysfunction in aged mice: A novel mechanism and therapeutic target.
Zhang C, Zhu X, Gao R, Chen H, Yan C, Liu W, Yang L, Zeng X, Yang H, Liu J, Li Q, Ma D, Zhu T, Chen C. Zhang C, et al. Mol Ther Nucleic Acids. 2025 May 8;36(2):102555. doi: 10.1016/j.omtn.2025.102555. eCollection 2025 Jun 10. Mol Ther Nucleic Acids. 2025. PMID: 40487353 Free PMC article.

References

1. Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet386, 896–912 (2015). 10.1016/S0140-6736(14)61393-3 - DOI - PubMed
1. Dickson, D. W. et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol.8, 1150–1157 (2009). 10.1016/S1474-4422(09)70238-8 - DOI - PubMed
1. Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature388, 839–840 (1997). 10.1038/42166 - DOI - PubMed
1. Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science276, 2045–2047 (1997). 10.1126/science.276.5321.2045 - DOI - PubMed
1. Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol.18, 1091–1102 (2019). 10.1016/S1474-4422(19)30320-5 - DOI - PMC - PubMed

LinkOut - more resources

Full Text Sources
- Nature Publishing Group
- PubMed Central

[1] Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet386, 896–912 (2015). 10.1016/S0140-6736(14)61393-3 - DOI - PubMed

[2] Kalia, L. V. & Lang, A. E. Parkinson’s disease. Lancet386, 896–912 (2015). 10.1016/S0140-6736(14)61393-3 - DOI - PubMed

[3] Dickson, D. W. et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol.8, 1150–1157 (2009). 10.1016/S1474-4422(09)70238-8 - DOI - PubMed

[4] Dickson, D. W. et al. Neuropathological assessment of Parkinson’s disease: refining the diagnostic criteria. Lancet Neurol.8, 1150–1157 (2009). 10.1016/S1474-4422(09)70238-8 - DOI - PubMed

[5] Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature388, 839–840 (1997). 10.1038/42166 - DOI - PubMed

[6] Spillantini, M. G. et al. α-Synuclein in Lewy bodies. Nature388, 839–840 (1997). 10.1038/42166 - DOI - PubMed

[7] Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science276, 2045–2047 (1997). 10.1126/science.276.5321.2045 - DOI - PubMed

[8] Polymeropoulos, M. H. et al. Mutation in the α-synuclein gene identified in families with Parkinson’s disease. Science276, 2045–2047 (1997). 10.1126/science.276.5321.2045 - DOI - PubMed

[9] Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol.18, 1091–1102 (2019). 10.1016/S1474-4422(19)30320-5 - DOI - PMC - PubMed

[10] Nalls, M. A. et al. Identification of novel risk loci, causal insights, and heritable risk for Parkinson’s disease: a meta-analysis of genome-wide association studies. Lancet Neurol.18, 1091–1102 (2019). 10.1016/S1474-4422(19)30320-5 - DOI - PMC - PubMed

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease

Affiliations

Loss-of-function variants in ITSN1 confer high risk of Parkinson's disease

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

LinkOut - more resources

Full Text Sources

Abstract

Conflict of interest statement

Figures

Similar articles

Cited by

References

Related information

LinkOut - more resources

Full Text Sources