New Results
Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy
Edwin Jabbari, Manuela M.X. Tan, Regina H. Reynolds, Kin Y. Mok, Raffaele Ferrari, David P. Murphy, Rebecca R. Valentino, Owen A. Ross, View ORCID ProfileDennis W. Dickson, Safa Al-Sarraj, Steve M. Gentleman, Kieren S.J. Allinson, Zane Jaunmuktane, Janice L. Holton, Tamas Revesz, Thomas T. Warner, View ORCID ProfileAndrew J. Lees, View ORCID ProfileMark R. Cookson, J. Raphael Gibbs, View ORCID ProfileJinhui Ding, Ruth Chia, Bryan J. Traynor, Sonja W. Scholz, View ORCID ProfileAlexander Pantelyat, Coralie Viollet, Clifton L. Dalgard, Olga Pletnikova, Juan C. Troncoso, Adam L. Boxer, Gesine Respondek, Günter U. Höglinger, David J. Burn, Nicola Pavese, Alexander Gerhard, Christopher Kobylecki, P. Nigel Leigh, Alistair Church, Michele T.M. Hu, James B. Rowe, Mina Ryten, John Hardy, Maryam Shoai, Huw R. Morris
doi: https://doi.org/10.1101/2020.02.04.932335
Edwin Jabbari
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
2Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK
Manuela M.X. Tan
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
2Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK
Regina H. Reynolds
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Kin Y. Mok
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Raffaele Ferrari
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
David P. Murphy
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
Rebecca R. Valentino
4Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
Owen A. Ross
4Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
Dennis W. Dickson
4Department of Neuroscience, Mayo Clinic, Jacksonville, Florida, USA
Safa Al-Sarraj
5MRC London Neurodegenerative Diseases Brain Bank, Institute of Psychiatry, King’s College London, London, UK
Steve M. Gentleman
6Multiple Sclerosis and Parkinson’s UK Brain Bank, Department of Brain Sciences, Imperial College London, London, UK
Kieren S.J. Allinson
7Department of Clinical Neurosciences, University of Cambridge; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Zane Jaunmuktane
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
9Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
Janice L. Holton
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
9Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
Tamas Revesz
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
9Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
Thomas T. Warner
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
9Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
Andrew J. Lees
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
9Queen Square Brain Bank for Neurological Disorders, UCL Queen Square Institute of Neurology, London, UK
Mark R. Cookson
10Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
J. Raphael Gibbs
10Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
Jinhui Ding
10Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
Ruth Chia
10Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
Bryan J. Traynor
10Laboratory of Neurogenetics, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA
11Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA
Sonja W. Scholz
11Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA
12Neurodegenerative Diseases Research Unit, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA
Alexander Pantelyat
11Department of Neurology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA
Coralie Viollet
13Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Clifton L. Dalgard
13Department of Anatomy, Physiology and Genetics, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
Olga Pletnikova
14Department of Pathology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA
Juan C. Troncoso
14Department of Pathology, Johns Hopkins University Medical Center, Baltimore, Maryland, USA
Adam L. Boxer
15Memory and Aging Center, University of California, San Francisco, USA
Gesine Respondek
16German Centre for Neurodegenerative Diseases (DZNE), Munich; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich; Department of Neurology, Hannover Medical School, Hannover, Germany
Günter U. Höglinger
16German Centre for Neurodegenerative Diseases (DZNE), Munich; Department of Neurology, Klinikum rechts der Isar, Technical University of Munich; Department of Neurology, Hannover Medical School, Hannover, Germany
David J. Burn
17Faculty of Medical Sciences, Newcastle University, Newcastle, UK
Nicola Pavese
17Faculty of Medical Sciences, Newcastle University, Newcastle, UK
Alexander Gerhard
18Department of Neurology, Salford Royal NHS Foundation Trust; Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
19Departments of Geriatrics and Nuclear Medicine, Universitätsklinikum Essen, Essen, Germany
Christopher Kobylecki
18Department of Neurology, Salford Royal NHS Foundation Trust; Manchester Academic Health Science Centre, University of Manchester, Manchester, UK
P. Nigel Leigh
20Department of Neuroscience, Brighton and Sussex Medical School, Brighton, UK
Alistair Church
21Department of Neurology, Royal Gwent Hospital, Newport, UK
Michele T.M. Hu
22Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
James B. Rowe
7Department of Clinical Neurosciences, University of Cambridge; Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
Mina Ryten
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
John Hardy
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
8Reta Lila Weston Institute, UCL Queen Square Institute of Neurology, London, UK
23Dementia Research Institute at UCL, UCL Queen Square Institute of Neurology, London, UK
24Institute for Advanced Study, The Hong Kong University of Science and Technology, Hong Kong SAR, China
Maryam Shoai
3Department of Neurodegenerative Disease, UCL Queen Square Institute of Neurology, London, UK
Huw R. Morris
1Department of Clinical and Movement Neurosciences, UCL Queen Square Institute of Neurology, London, UK
2Movement Disorders Centre, UCL Queen Square Institute of Neurology, London, UK
Abstract
The genetic basis of variation in the rate of disease progression of primary tauopathies has not been determined. In two independent progressive supranuclear palsy cohorts, we show that common variation at the LRRK2 locus determines survival from motor symptom onset to death, possibly through regulation of gene expression. This links together genetic risk in alpha-synuclein and tau disorders, and suggests that modulation of proteostasis and neuro-inflammation by LRRK2 inhibitors may have a therapeutic role across disorders.
Copyright
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
Posted February 04, 2020.
Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy
Edwin Jabbari, Manuela M.X. Tan, Regina H. Reynolds, Kin Y. Mok, Raffaele Ferrari, David P. Murphy, Rebecca R. Valentino, Owen A. Ross, Dennis W. Dickson, Safa Al-Sarraj, Steve M. Gentleman, Kieren S.J. Allinson, Zane Jaunmuktane, Janice L. Holton, Tamas Revesz, Thomas T. Warner, Andrew J. Lees, Mark R. Cookson, J. Raphael Gibbs, Jinhui Ding, Ruth Chia, Bryan J. Traynor, Sonja W. Scholz, Alexander Pantelyat, Coralie Viollet, Clifton L. Dalgard, Olga Pletnikova, Juan C. Troncoso, Adam L. Boxer, Gesine Respondek, Günter U. Höglinger, David J. Burn, Nicola Pavese, Alexander Gerhard, Christopher Kobylecki, P. Nigel Leigh, Alistair Church, Michele T.M. Hu, James B. Rowe, Mina Ryten, John Hardy, Maryam Shoai, Huw R. Morris
bioRxiv 2020.02.04.932335; doi: https://doi.org/10.1101/2020.02.04.932335
Common variation at the LRRK2 locus is associated with survival in the primary tauopathy progressive supranuclear palsy
Edwin Jabbari, Manuela M.X. Tan, Regina H. Reynolds, Kin Y. Mok, Raffaele Ferrari, David P. Murphy, Rebecca R. Valentino, Owen A. Ross, Dennis W. Dickson, Safa Al-Sarraj, Steve M. Gentleman, Kieren S.J. Allinson, Zane Jaunmuktane, Janice L. Holton, Tamas Revesz, Thomas T. Warner, Andrew J. Lees, Mark R. Cookson, J. Raphael Gibbs, Jinhui Ding, Ruth Chia, Bryan J. Traynor, Sonja W. Scholz, Alexander Pantelyat, Coralie Viollet, Clifton L. Dalgard, Olga Pletnikova, Juan C. Troncoso, Adam L. Boxer, Gesine Respondek, Günter U. Höglinger, David J. Burn, Nicola Pavese, Alexander Gerhard, Christopher Kobylecki, P. Nigel Leigh, Alistair Church, Michele T.M. Hu, James B. Rowe, Mina Ryten, John Hardy, Maryam Shoai, Huw R. Morris
bioRxiv 2020.02.04.932335; doi: https://doi.org/10.1101/2020.02.04.932335
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