Manuela M. X. Tan, Michael A. Lawton, Miriam I. Pollard, Emmeline Brown, Raquel Real, Alejandro Martinez Carrasco, Samir Bekadar, Edwin Jabbari, Regina H. Reynolds, Hirotaka Iwaki, Cornelis Blauwendraat, Sofia Kanavou, Leon Hubbard, Naveed Malek, Katherine A. Grosset, Nin Bajaj, Roger A. Barker, David J. Burn, Catherine Bresner, Thomas Foltynie, Nicholas W. Wood, Caroline H. Williams-Gray, Ole A. Andreassen, Mathias Toft, Alexis Elbaz, Fanny Artaud, Alexis Brice, Jean-Christophe Corvol, Jan Aasly, Matthew J. Farrer, Michael A. Nalls, Andrew B. Singleton, Nigel M. Williams, Yoav Ben-Shlomo, John Hardy, Michele T. M. Hu, Donald G. Grosset, Maryam Shoai, Lasse Pihlstrøm, Huw R. Morris
{"title":"Genome-wide determinants of mortality and motor progression in Parkinson’s disease","authors":"Manuela M. X. Tan, Michael A. Lawton, Miriam I. Pollard, Emmeline Brown, Raquel Real, Alejandro Martinez Carrasco, Samir Bekadar, Edwin Jabbari, Regina H. Reynolds, Hirotaka Iwaki, Cornelis Blauwendraat, Sofia Kanavou, Leon Hubbard, Naveed Malek, Katherine A. Grosset, Nin Bajaj, Roger A. Barker, David J. Burn, Catherine Bresner, Thomas Foltynie, Nicholas W. Wood, Caroline H. Williams-Gray, Ole A. Andreassen, Mathias Toft, Alexis Elbaz, Fanny Artaud, Alexis Brice, Jean-Christophe Corvol, Jan Aasly, Matthew J. Farrer, Michael A. Nalls, Andrew B. Singleton, Nigel M. Williams, Yoav Ben-Shlomo, John Hardy, Michele T. M. Hu, Donald G. Grosset, Maryam Shoai, Lasse Pihlstrøm, Huw R. Morris","doi":"10.1038/s41531-024-00729-8","DOIUrl":null,"url":null,"abstract":"<p>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 <b>APOE</b> ε4 allele on mortality in PD. We also identified a locus within the <b>TBXAS1</b> gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near <b>MORN1</b>, <b>ASNS</b>, <b>PDE5A</b>, and <b>XPO1</b>. Only the non-Gaucher disease causing <b>GBA1</b> 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.</p>","PeriodicalId":19706,"journal":{"name":"NPJ Parkinson's Disease","volume":null,"pages":null},"PeriodicalIF":6.7000,"publicationDate":"2024-06-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"NPJ Parkinson's Disease","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1038/s41531-024-00729-8","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"NEUROSCIENCES","Score":null,"Total":0}
引用次数: 0
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.
期刊介绍:
npj Parkinson's Disease is a comprehensive open access journal that covers a wide range of research areas related to Parkinson's disease. It publishes original studies in basic science, translational research, and clinical investigations. The journal is dedicated to advancing our understanding of Parkinson's disease by exploring various aspects such as anatomy, etiology, genetics, cellular and molecular physiology, neurophysiology, epidemiology, and therapeutic development. By providing free and immediate access to the scientific and Parkinson's disease community, npj Parkinson's Disease promotes collaboration and knowledge sharing among researchers and healthcare professionals.