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

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

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

NPJ Parkinsons Dis. 2024 Jun 7;10(1):113. doi: 10.1038/s41531-024-00729-8.

Authors

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. [email protected].
² Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK. [email protected].
³ UCL Movement Disorders Centre, University College London, London, UK. [email protected].
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. [email protected].
³⁶ UCL Movement Disorders Centre, University College London, London, UK. [email protected].
³⁷ Aligning Science Across Parkinson's (ASAP) Collaborative Research Network, Chevy Chase, MD, 20815, USA. [email protected].

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.

Abstract

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