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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\n                    <jats:bold>APOE<\/jats:bold>\n                    \u03b54 allele on mortality in PD. We also identified a locus within the\n                    <jats:bold>TBXAS1<\/jats:bold>\n                    gene encoding thromboxane A synthase 1 associated with mortality in PD. We also report 4 independent loci associated with motor progression in or near\n                    <jats:bold>MORN1<\/jats:bold>\n                    ,\n                    <jats:bold>ASNS<\/jats:bold>\n                    ,\n                    <jats:bold>PDE5A<\/jats:bold>\n                    , and\n                    <jats:bold>XPO1<\/jats:bold>\n                    . Only the non-Gaucher disease causing\n                    <jats:bold>GBA1<\/jats:bold>\n                    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.\n                  <\/jats:p>","DOI":"10.1038\/s41531-024-00729-8","type":"journal-article","created":{"date-parts":[[2024,6,7]],"date-time":"2024-06-07T09:02:01Z","timestamp":1717750921000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Genome-wide determinants of mortality and motor progression in Parkinson\u2019s disease"],"prefix":"10.1038","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5835-669X","authenticated-orcid":false,"given":"Manuela M. 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She has received grant support from Parkinson\u2019s UK, the Michael J Fox Foundation, and South-Eastern Norway Regional Health Authority (Helse S\u00f8r-\u00d8st). MAL received fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust. KG is an independent medical consultant and receives payments from the University of Glasgow. She has no other fees or honoraria to report. J-CC has served on advisory boards for Biogen, Denali, Idorsia, Prevail Therapeutic, Servier, Theranexus, UCB; and received grants from Sanofi and the Michael J Fox Foundation outside of this work. RHR is currently employed by CoSyne Therapeutics (Lead Computational Biologist). All work performed for this publication was performed in her own time, and not as a part of her duties as an employee. MAN\u2019s participation in this project was part of a competitive contract awarded to DataTecnica LLC by the National Institutes of Health to support open science research. MAN also currently serves on the scientific advisory board for Character Bio Inc and is a scientific founder at Neuron23 Inc and owns stock. ABS is Associate Editor of npj Parkinson\u2019s Disease. ABS was not involved in the journal\u2019s review of, or decisions related to, this manuscript. OAA is a consultant to HealthLytix. CWG is employed by the University of Cambridge and supported by the Medical Research Council (MR\/R007446\/1 and MR\/W029235\/1) and the NIHR Cambridge Biomedical Research Centre (NIHR 203312). She has received research funding from the Cambridge Centre for Parkinson-Plus, Cure Parkinson\u2019s, Parkinson\u2019s UK, The Evelyn Trust, The Rosetrees Trust, Addenbrooke\u2019s Charitable Trust and the Michael J Fox Foundation; speaker payments from GSK and World Parkinson\u2019s Coalition; and consulting fees from Evidera Inc. RAB has served as an advisor to UCB; BlueRock Therapeutics; Novo Nordisk; Aspen Neuroscience, UCB and Transine Therapeutics. He has received lecture fees from Novo Nordisk. He has received grant support from the MRC, Wellcome, Parkinson\u2019s UK, Cure Parkinson\u2019s Trust, EU, Novo Nordisk, DRI, and ASAP. This research was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. He has received royalties from Wiley and Springer-Nature. DGG is an employee of the University of Glasgow. In the past 12 months, he reports consultancy fees from the Glasgow Memory Clinic; honoraria for chairing or attending meetings from AbbVie and BIAL Pharma. LP has received grant support from the National Health Association, Norway, the Michael J Fox Foundation, and South-Eastern Norway Regional Health Authority (Helse S\u00f8r-\u00d8st). HRM is employed by UCL. In the last 12 months, he reports paid consultancy from Roche and Amylyx; lecture fees\/honoraria - BMJ, Kyowa Kirin, Movement Disorders Society. Research Grants from Parkinson\u2019s UK, Cure Parkinson\u2019s Trust, PSP Association, Medical Research Council, Michael J Fox Foundation. HRM is a co-applicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT\/GB2012\/052140).","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"113"}}