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A common polymorphism in SNCA is associated with accelerated motor decline in GBA-Parkinson’s disease
  1. Thomas B Stoker1,2,
  2. Marta Camacho1,
  3. Sophie Winder-Rhodes1,
  4. Ganqiang Liu3,4,5,
  5. Clemens R Scherzer4,5,
  6. Thomas Foltynie6,
  7. Roger A Barker1,2,
  8. Caroline H Williams-Gray1
  1. 1 John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, UK
  2. 2 Wellcome Trust ‑ Medical Research Council Stem Cell Institute, University of Cambridge, Cambridge, UK
  3. 3 School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong, China
  4. 4 Advanced Center for Parkinson's Disease Research, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
  5. 5 Precision Neurology Program, Harvard Medical School, Brigham and Women's Hospital, Boston, Massachusetts, USA
  6. 6 Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, London, UK
  1. Correspondence to Dr Thomas B Stoker, John van Geest Centre for Brain Repair, Department of Clinical Neurosciences, University of Cambridge, Cambridge, Cambridgeshire CB2 0PY, UK; tbs26{at}cam.ac.uk

https://doi.org/10.1136/jnnp-2019-322210

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    A growing number of genetic susceptibility factors have been identified for Parkinson’s disease (PD). The combination of inherited risk variants is likely to affect not only risk of developing PD but also its clinical course. Variants in the GBA gene are particularly common, being found in approximately 5% to 10% of patients, and they lead to more rapid disease progression.1 However, the effect of concomitant genetic risk factors on disease course in GBA-PD is not known.

    The aggregation of α-synuclein, encoded by the SNCA gene, is central to the pathogenesis of PD. The SNCA rs356219 A/G polymorphism alters the risk of developing PD, with homozygotes for guanine (G/G) having an increased risk compared with carriers of an adenine (G/A or A/A) at this locus.2 The relationship between glucocerebrosidase (the enzyme encoded by the GBA gene) and α-synuclein is complex. These proteins have been shown to interact directly in vitro, as well as to influence the intracellular levels and processing of each other, potentially in a bidirectional feedback loop.3 4 Interestingly, a recent genome-wide association study found that the presence of this SNCA polymorphism was associated with an increased likelihood of developing PD in GBA mutation carriers.5 We therefore hypothesised that the presence of the SNCA rs356219 polymorphism would accelerate the clinical course of GBA variant-associated PD. Here, we report on the effect of this SNCA polymorphism on clinical outcomes within the GBA-PD population.

    Longitudinal data from GBA-variant carriers were analysed from the community-based ‘Cambridgeshire Incidence of Parkinson’s disease from General Practice to Neurologist’ (CamPaIGN) cohort (n=142).6 This study was approved by the local ethics committee and written informed consent was obtained from all subjects. Newly diagnosed patients were followed up with assessments every 2 years for up to 18 years. Time to …

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