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

Background There are 90 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. Methods We studied 6,766 PD patients, over 15,340 visits with a mean follow-up of between 4.2 and 15.7 years and carried out a genome wide survival study for time to a motor progression endpoint, defined by reaching Hoehn and Yahr stage 3 or greater, and death (mortality). Findings There was a robust effect of the APOE ε4 allele on mortality in PD. We identified three novel loci for mortality and motor progression, and nominated genes based on physical proximity and/or expression quantitative trait loci data. One locus within the TBXAS1 gene encoding thromboxane A synthase 1 was associated with mortality in PD (HR = 2.04 [95% CI 1.63 to 2.56], p-value = 7.71 x 10-10). Another locus near the SYT10 gene encoding synaptotagmin 10 was associated with mortality just above genome-wide significance (HR=1.36 [95% CI 1.21 to 1.51], p-value=5.31×10-8). We also report 4 independent loci associated with motor progression: the top locus within MORN1 (HR=2.76 [95% CI 1.97 to 3.87], p-value=3.1×10-9), the second most significant locus near ASNS , the third most significant locus near PDE5A , and a fourth locus within XPO1 . We have nominated causal genes based on physical position, however we also discuss other possible causal genes based on expression quantitative trait loci, colocalization analysis, and tagging of rare variants. Only the non-Gaucher disease causing GBA1 PD risk variant E326K, of the known PD risk variants, was associated with mortality in PD. Interpretation We report six novel loci associated with PD motor progression or mortality. Further work is needed to understand the links between these genomic variants and the underlying disease biology. However, thromboxane synthesis, vesicular peptidergic neurotransmitter release, and phosphodiesterase inhibition may represent new candidates for disease modification in PD. Funding sources Parkinson’s UK, Aligning Science Across Parkinson’s through the Michael J Fox Foundation for Parkinson’s Research, Southern and Eastern Norway Regional Health Authority ### Competing Interest Statement MMXT is employed by Oslo University Hospital. She has received grant support from Parkinson's UK, the Michael J Fox Foundation, and South-Eastern Norway Regional Health Authority. 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. MAN's participation in this project was part of a competitive contract awarded to Data Tecnica International LLC by the National Institutes of Health to support open science research, he also currently serves on the scientific advisory board for Clover Therapeutics and is an advisor to Neuron23 Inc as a data science fellow. OAA is a consultant to HealthLytix. CWG is employed by the University of Cambridge and holds a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1). In the last 36 months, she has received research funding from the Cambridge Centre for Parkinson-Plus, the NIHR Cambridge Biomedical Research Centre, Cure Parkinson's, Parkinson's UK, The Evelyn Trust, and the Michael J Fox Foundation; speaker payments from GSK and World Parkinson's 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's UK, Cure Parkinson's 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. 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's UK, Cure Parkinson's 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). ### Funding Statement Parkinson's UK, Aligning Science Across Parkinson's through the Michael J Fox Foundation for Parkinson's Research, Southern and Eastern Norway Regional Health Authority ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Tracking Parkinson's: West of Scotland Research Ethics Service (WoSRES) Research Ethics Committee gave ethical approval for this study (ref 11/AL/0163). Oxford Discovery: NRES Committee, South Central Oxford A Research Ethics Committee gave ethical approval for this study (ref 16/SC/0108). CamPaIGN: Cambridge Research Ethics Committee gave ethical approval for this study. Cambridge PD Research Clinic: Cambridge Research Ethics Committee gave ethical approval for this study. PPMI: The Research Subjects Review Board at the University of Rochester approved the PPMI study protocol. UK Biobank: UK Biobank has approval from the North West Multi-centre Research Ethics Committee (MREC) as a Research Tissue Bank (RTB). QSBB: London Central Research Ethics Committee gave ethical approval for this research tissue bank (ref 18/LO/0721). DIGPD: the Ethical committee Ile-De-France VI gave ethical approval for this study (ID project: 2009-A00109-48). Calypso: Wales Research Ethics Committee 3 gave ethical approval for this study. Trondheim: the Ethics Committee of Central Norway gave ethical approval for this study (ref 2011/1137). Oslo: the Regional Committee for Medical Research Ethics in South-East Norway gave ethical approval for this study. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes GWAS summary statistics are available for download at: (DOI: 10.5281/zenodo.8017385). All code for our analyses is publicly available at (DOI: 10.5281/zenodo.7923843). Tracking Parkinson's data is available through the Tracking Parkinson's portal: . The Oxford Parkinson's Disease Centre Discovery Cohort data () are available on request (Michele Hu, michele.hu{at}ndcn.ox.ac.uk). The Cambridgeshire Parkinson's Incidence from GP to Neurologist (CamPaIGN) () data and the Cambridge clinic data are available on request (Caroline Williams-Gray/ Roger Barker; chm27{at}cam.ac.uk). Parkinson's Progression Markers Initiative (PPMI) data was accessed from the PPMI platform: . Queen Square Brain Bank for Neurological Disorders (QSBB) data are available upon request (qsbbmtas{at}ucl.ac.uk). UK Biobank data were accessed through the UK Biobank: . Drug Interaction With Genes in Parkinson's Disease (DIGPD) data () are available upon request (Jean-Christophe Corvol, jean-christophe.corvol{at}aphp.fr). Calypso data are available on request to the study team (Huw Morris, h.morris{at}ucl.ac.uk). The Trondheim Parkinson's Disease Study (Trondheim) data are available on request (). The Oslo Parkinson's Disease data are available on request (Lasse Pihlstrom/ Mathias Toft, lasse.pihlstrom{at}medisin.uio.no). * FUMA : Functional Mapping and Annotation of GWAS GWAS : Genome-Wide Association Study H&Y : Hoehn and Yahr LD : Linkage Disequilibrium MDS-UPDRS : Movement Disorder Society Unified Parkinson’s Disease Rating Scale PD : Parkinson’s Disease PPMI : Parkinson’s Progression Markers Initiative SNP : Single Nucleotide Polymorphism SD : Standard Deviation SE : Standard Error UKB : UK Biobank.