Genetics of validated Parkinson's disease subtypes in the Oxford Discovery and Tracking Parkinson's cohorts.

Autor:	Lawton M; Population Health Sciences, University of Bristol Medical School, Bristol, UK Michael.Lawton@bristol.ac.uk., Tan MM; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Ben-Shlomo Y; Population Health Sciences, University of Bristol Medical School, Bristol, UK., Baig F; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Molecular and Clinical Sciences Institute, St. George's University of London, London, UK., Barber T; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK., Klein JC; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK., Evetts SG; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK., Millin S; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.; Department of Physiology, Anatomy and Genetics, University of Oxford, Oxford, UK., Malek N; Department of Neurology, Queen's Hospital, Romford, Essex, UK., Grosset K; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK., Barker RA; Cambridge Centre for Brain Repair, University of Cambridge, Cambridge, UK., Williams N; Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, UK., Burn DJ; Faculty of Medical Sciences, Newcastle University, Newcastle, UK., Foltynie T; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK., Morris HR; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK.; UCL Movement Disorders Centre, University College London, London, UK., Wood N; Department of Clinical and Movement Neurosciences, Queen Square Institute of Neurology, University College London, London, UK., Grosset DG; Department of Neurology, Institute of Neurological Sciences, Queen Elizabeth University Hospital and University of Glasgow, Glasgow, UK., Hu MT; Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK.; Oxford Parkinson's Disease Centre, University of Oxford, Oxford, UK.
Jazyk:	angličtina
Zdroj:	Journal of neurology, neurosurgery, and psychiatry [J Neurol Neurosurg Psychiatry] 2022 Jun 22. Date of Electronic Publication: 2022 Jun 22.
DOI:	10.1136/jnnp-2021-327376
Abstrakt:	Objectives: To explore the genetics of four Parkinson's disease (PD) subtypes that have been previously described in two large cohorts of patients with recently diagnosed PD. These subtypes came from a data-driven cluster analysis of phenotypic variables. Methods: We looked at the frequency of genetic mutations in glucocerebrosidase (GBA) and leucine-rich repeat kinase 2 against our subtypes. Then we calculated Genetic Risk Scores (GRS) for PD, multiple system atrophy, progressive supranuclear palsy, Lewy body dementia, and Alzheimer's disease. These GRSs were regressed against the probability of belonging to a subtype in the two independent cohorts and we calculated q-values as an adjustment for multiple testing across four subtypes. We also carried out a Genome-Wide Association Study (GWAS) of belonging to a subtype. Results: A severe disease subtype had the highest rates of patients carrying GBA mutations while the mild disease subtype had the lowest rates (p=0.009). Using the GRS, we found a severe disease subtype had a reduced genetic risk of PD (p=0.004 and q=0.015). In our GWAS no individual variants met genome wide significance (<5×10e-8) although four variants require further follow-up, meeting a threshold of <1×10e-6. Conclusions: We have found that four previously defined PD subtypes have different genetic determinants which will help to inform future studies looking at underlying disease mechanisms and pathogenesis in these different subtypes of disease. Competing Interests: Competing interests: ML: received fees for advising on a secondary analysis of an RCT sponsored by North Bristol NHS trust. MMXT: reports no disclosures. YB-S: reports no disclosures. FB: reports no disclosures. TB: reports no disclosures. JCK: reports no disclosures. SGE: reports no disclosures. SM: reports no disclosures. NM: reports no disclosures. KG: reports no disclosures. RAB: received grants from Parkinson’s UK, NIHR, Cure Parkinson’s Trust, Evelyn Trust, Rosetrees Trust, MRC and EU along with payment for advisory board attendance from Oxford Biomedica, Aspen Neuroscience, UCB, BlueRock Therapeutics, Novo Nordisk and LCT, and honoraria from Wiley and Springer. NW: reports no disclosures. DJB: received grants from NIHR, Wellcome Trust, GlaxoSmithKline, Parkinson’s UK, and Michael J Fox Foundation. TF: grants from National Institute of Health Research, Michael J Fox Foundation, John Black Charitable Foundation, Cure Parkinson’s Trust, Innovate UK, Janet Owens Research Fellowship, Van Andel Research Institute and Defeat MSA. Advisory Boards for Peptron, Voyager Therapeutics, Handl therapeutics, Living Cell Technologies, Bial grants from Welsh Assembly Government, personal fees from Teva, personal fees from Abbvie, personal fees from Teva, personal fees from UCB, personal fees from Boehringer-Ingelheim, personal fees from GSK, non-financial support from Teva, grants from Ipsen Fund, non-financial support from Medtronic, grants from MNDA, grants from PSP Association, grants from CBD Solutions, grants from Drake Foundation, personal fees from Acorda, outside the submitted work; In addition, HRM has a patent. HRM is a coapplicant on a patent application related to C9ORF72 - Method for diagnosing a neurodegenerative disease (PCT/GB2012/052140) pending. NW: reports Funding from Aligning science against Parkinsons (ASAP). He has also received consultancy fees from GSK. DGG: received payment for advisory board attendance from Merz Pharma, Vectura plc, and consultancy fees from the GM clinic. Grant support from Parkinson’s UK, the Neurosciences Foundation, and Michael’s Movers. MT-MH: received payment for Advisory Board attendance/consultancy for Biogen, Roche, CuraSen Therapeutics, Evidera, Manus Neurodynamica. She received funding/grant support from Parkinson’s UK, Oxford NIHR BRC, University of Oxford, CPT, Lab10X, NIHR, Michael J Fox Foundation, H2020 European Union, GE Healthcare and the PSP Association. MT-MH is a coapplicant on a patent application related to smartphone predictions in Parkinson’s (PCT/GB2019/052522) pending. (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY. Published by BMJ.)
Databáze:	MEDLINE
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