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

Manuela M X Tan^{1

2

3}, Michael A Lawton⁴, Miriam I Pollard⁵, Emmeline Brown⁵, Raquel Real^{5

6

7}, Alejandro Martinez Carrasco^{5

6

7}, Samir Bekadar⁸, Edwin Jabbari^{5

6}, Regina H Reynolds^{7

9}, Hirotaka Iwaki^{10

11

12}, Cornelis Blauwendraat^{10

12}, Sofia Kanavou⁴, Leon Hubbard¹³, Naveed Malek¹⁴, Katherine A Grosset¹⁴, Nin Bajaj¹⁵, Roger A Barker^{7

16

17}, David J Burn¹⁸, Catherine Bresner¹³, Thomas Foltynie^{5

6}, Nicholas W Wood^{5

6

7}, Caroline H Williams-Gray¹⁶, Ole A Andreassen^{19

20}, Mathias Toft^{21

20}, Alexis Elbaz²², Fanny Artaud²², Alexis Brice⁸, Jean-Christophe Corvol⁸, Jan Aasly^{23

24}, Matthew J Farrer²⁵, Michael A Nalls^{10

11

12}, Andrew B Singleton^{10

12}, Nigel M Williams¹³, Yoav Ben-Shlomo⁴, John Hardy^{6

7

26

27

28

29

30}, Michele T M Hu^{31

32

33}, Donald G Grosset³⁴, Maryam Shoai^{7

26

27}, Lasse Pihlstrøm²¹, Huw R Morris^{35

36

37}

Affiliations

¹ Department of Neurology, Oslo University Hospital, Oslo, Norway. manuela.tan@medisin.uio.no.
² Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK. manuela.tan@medisin.uio.no.
³ UCL Movement Disorders Centre, University College London, London, UK. manuela.tan@medisin.uio.no.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
⁶ UCL Movement Disorders Centre, University College London, London, UK.
⁷ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁸ Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Departement of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.
⁹ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
¹⁰ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹¹ Data Tecnica, Washington DC, USA.
¹² Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.
¹³ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
¹⁴ Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
¹⁵ Clinical Neurosciences, University of Nottingham, Nottingham, UK.
¹⁶ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹⁷ Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
¹⁸ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹⁹ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²⁰ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
²¹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
²² Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, "Exposome and Heredity" team, CESP, 94807, Villejuif, France.
²³ Department of Neurology, St. Olavs Hospital, Trondheim, Norway.
²⁴ Department of Neuromedicine and Movement Science (INB), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²⁵ Department of Neurology, University of Florida, Gainesville, FL, USA.
²⁶ Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
²⁷ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
²⁸ UK Dementia Research Institute, University College London, London, UK.
²⁹ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.
³⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
³¹ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.
³² Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
³³ Department of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
³⁴ School of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
³⁵ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK. h.morris@ucl.ac.uk.
³⁶ UCL Movement Disorders Centre, University College London, London, UK. h.morris@ucl.ac.uk.
³⁷ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. h.morris@ucl.ac.uk.

PMID: 38849413
PMCID: PMC11161485
DOI: 10.1038/s41531-024-00729-8

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

Manuela M X Tan et al. NPJ Parkinsons Dis. 2024.

. 2024 Jun 7;10(1):113.

doi: 10.1038/s41531-024-00729-8.

Authors

Affiliations

¹ Department of Neurology, Oslo University Hospital, Oslo, Norway. manuela.tan@medisin.uio.no.
² Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK. manuela.tan@medisin.uio.no.
³ UCL Movement Disorders Centre, University College London, London, UK. manuela.tan@medisin.uio.no.
⁴ Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
⁵ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.
⁶ UCL Movement Disorders Centre, University College London, London, UK.
⁷ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA.
⁸ Sorbonne University, Paris Brain Institute - ICM, Inserm, CNRS, Assistance Publique Hôpitaux de Paris, Departement of Neurology, Hôpital Pitié-Salpêtrière, Paris, France.
⁹ Genetics and Genomic Medicine, Great Ormond Street Institute of Child Health, University College London, London, UK.
¹⁰ Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, MD, USA.
¹¹ Data Tecnica, Washington DC, USA.
¹² Center for Alzheimer's and Related Dementias, National Institutes of Health, Bethesda, MD, USA.
¹³ Institute of Psychological Medicine and Clinical Neurosciences, MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff University, Cardiff, UK.
¹⁴ Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital, Glasgow, UK.
¹⁵ Clinical Neurosciences, University of Nottingham, Nottingham, UK.
¹⁶ John Van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK.
¹⁷ Cambridge Stem Cell Institute, University of Cambridge, Cambridge, UK.
¹⁸ Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK.
¹⁹ NORMENT, Division of Mental Health and Addiction, Oslo University Hospital, Oslo, Norway.
²⁰ Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway.
²¹ Department of Neurology, Oslo University Hospital, Oslo, Norway.
²² Paris-Saclay University, UVSQ, Inserm, Gustave Roussy, "Exposome and Heredity" team, CESP, 94807, Villejuif, France.
²³ Department of Neurology, St. Olavs Hospital, Trondheim, Norway.
²⁴ Department of Neuromedicine and Movement Science (INB), Faculty of Medicine and Health Sciences, Norwegian University of Science and Technology (NTNU), Trondheim, Norway.
²⁵ Department of Neurology, University of Florida, Gainesville, FL, USA.
²⁶ Department of Neurodegenerative Diseases, Queen Square Institute of Neurology, University College London, London, UK.
²⁷ Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK.
²⁸ UK Dementia Research Institute, University College London, London, UK.
²⁹ National Institute for Health Research (NIHR) University College London Hospitals Biomedical Research Centre, London, UK.
³⁰ Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China.
³¹ Nuffield Department of Clinical Neurosciences, Division of Clinical Neurology, University of Oxford, Oxford, UK.
³² Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
³³ Department of Clinical Neurology, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.
³⁴ School of Neuroscience and Psychology, University of Glasgow, Glasgow, UK.
³⁵ Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK. h.morris@ucl.ac.uk.
³⁶ UCL Movement Disorders Centre, University College London, London, UK. h.morris@ucl.ac.uk.
³⁷ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. h.morris@ucl.ac.uk.

PMID: 38849413
PMCID: PMC11161485
DOI: 10.1038/s41531-024-00729-8

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.

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Conflict of 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 (Helse Sør-Øst). 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’s 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’s Disease. ABS was not involved in the journal’s 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’s, Parkinson’s UK, The Evelyn Trust, The Rosetrees Trust, Addenbrooke’s Charitable 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. LP has received grant support from the National Health Association, Norway, the Michael J Fox Foundation, and South-Eastern Norway Regional Health Authority (Helse Sør-Øst). 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).

Figures

**Fig. 1. GWAS meta-analysis of mortality.**
a The Manhattan plot showing two GWAS significant loci after meta-analysis. The blue dashed line indicates the threshold for genome-wide significance, p = 5 × 10⁻⁸. SNPs highlighted in red have p-value < 5 × 10⁻⁹. SNPs highlighted in orange have p-value < 5 x 10⁻⁸. One nominal association in Chromosome 12 is also annotated with the nearest gene, *SYT10* (p = 5.3 × 10⁻⁸). b Forest plot for the top SNP rs429358 in Chromosome 19, in *APOE*. c Forest plot for the top SNP rs4726467 in Chromosome 7, in *TBXAS1*. d Forest plot for the top SNP rs10437796 in Chromosome 12, near *SYT10*. BP Base Pair, CI Confidence Interval, GWAS Genome Wide Association Study. HR Hazard Ratio. SNP Single Nucleotide Polymorphism.

**Fig. 2. GWAS meta-analysis of progression to Hoehn and Yahr stage 3 or greater (H&Y3+).**
Note that the loci in the Manhattan plot and the forest plots have been labelled with the physically closest genes, though these may not necessarily be the causal genes. a The Manhattan plot showing four GWAS significant loci after meta-analysis. The blue dashed line indicates the threshold for genome-wide significance, p = 5 × 10⁻⁸. SNPs highlighted in red have p-value < 5 × 10⁻⁹. SNPs highlighted in orange have p-value < 5 × 10⁻⁸. b Forest plot for the top SNP rs115217673 in Chromosome 1, in *MORN1*. c Forest plot for the top SNP rs145274312 in Chromosome 7, near *ASNS*. d Forest plot for the top SNP rs113120976 in Chromosome 4, near *PDE5A*. e Forest plot for the top SNP rs141421624 in Chromosome 2, in *XPO1*. BP Base Pair, CI Confidence Interval, GWAS Genome Wide Association Study. HR Hazard Ratio. SNP Single Nucleotide Polymorphism.

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References

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

Affiliations

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

Authors

Affiliations

Abstract

Conflict of interest statement

Figures

References

Grants and funding

LinkOut - more resources

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