Genome-wide determinants of mortality and motor progression in Parkinson’s disease

Tan, Manuela M. X., Lawton, Michael A., Pollard, Miriam I., Brown, Emmeline, Real, Raquel, Carrasco, Alejandro Martinez, Bekadar, Samir, Jabbari, Edwin, Reynolds, Regina H., Iwaki, Hirotaka, Blauwendraat, Cornelis, Kanavou, Sofia, Hubbard, Leon, Malek, Naveed, Grosset, Katherine A., Bajaj, Nin, Barker, Roger A., Burn, David J., Bresner, Catherine, Foltynie, Thomas, Wood, Nicholas W., Williams-Gray, Caroline H., Andreassen, Ole A., Toft, Mathias, Elbaz, Alexis, Artaud, Fanny, Brice, Alexis, Corvol, Jean-Christophe, Aasly, Jan, Farrer, Matthew J., Nalls, Michael A., Singleton, Andrew B., Williams, Nigel M. ORCID: https://orcid.org/0000-0003-1177-6931, Ben-Shlomo, Yoav, Hardy, John, Hu, Michele T. M., Grosset, Donald G., Shoai, Maryam, Pihlstrøm, Lasse and Morris, Huw R. 2024. Genome-wide determinants of mortality and motor progression in Parkinson’s disease. npj Parkinson's Disease 10 (1) , 113. 10.1038/s41531-024-00729-8

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Abstract

There are 90 independent genome-wide significant genetic risk variants for Parkinson’s disease (PD) but currently only five nominated loci for PD progression. The biology of PD progression is likely to be of central importance in defining mechanisms that can be used to develop new treatments. We studied 6766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out genome-wide survival studies for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). There was a robust effect of the APOE ε4 allele on mortality in PD. We also identified a locus within the TBXAS1 gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near MORN1, ASNS, PDE5A, and XPO1. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, these may represent new candidates for disease modification in PD.

Item Type:	Article
Date Type:	Published Online
Status:	Published
Schools:	Medicine
Additional Information:	License information from Publisher: LICENSE 1: URL: http://creativecommons.org/licenses/by/4.0/, Type: open-access
Publisher:	Nature Research
Date of First Compliant Deposit:	10 June 2024
Date of Acceptance:	24 May 2024
Last Modified:	10 Jun 2024 09:16
URI:	https://orca.cardiff.ac.uk/id/eprint/169641

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