Impact of GBA1 variants on long-term clinical progression and mortality in incident Parkinson's disease.

INTRODUCTION: Variants in the GBA1 gene have been identified as a common risk factor for Parkinson's disease (PD). In addition to pathogenic mutations (those associated with Gaucher disease), a number of 'non-pathogenic' variants also occur at increased frequency in PD. Previous studies have reported that pathogenic variants adversely affect the clinical course of PD. The role of 'non-pathogenic' GBA1 variants on PD course is less clear. In this study, we report the effect of GBA1 variants in incident PD patients with long-term follow-up. METHODS: The study population consisted of patients in the Cambridgeshire Incidence of Parkinson's disease from General Practice to Neurologist and Parkinsonism: Incidence, Cognition and Non-motor heterogeneity in Cambridgeshire cohorts. Patients were grouped into non-carriers, carriers of 'non-pathogenic' GBA1 variants and carriers of pathogenic GBA1 mutations. Survival analyses for time to development of dementia, postural instability and death were carried out. Cox regression analysis controlling for potential confounders were used to determine the impact of GBA1 variants on these outcome measures. RESULTS: GBA1 variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic' GBA1 variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic GBA1 variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. DISCUSSION: GBA1 variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.The CamPaIGN study has been supported by funding from the Wellcome Trust, the Medical Research Council, Parkinson’s UK and the Patrick Berthoud Trust. The PICNICS study has been supported by funding from the Cure Parkinson’s Trust, the Van Geest Foundation, the MRC and Parkinson’s UK. This work has also been supported by the National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre Dementia and Neurodegeneration Theme (Grant Reference Number 146281). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. TBS received financial support from the Cure Parkinson’s Trust. CRS' work is supported in part by NIH grants R01AG057331, U01NS100603, R01AG057331, and the American Parkinson Disease Association. Illumina MEGA ChIP genotyping was made possible by a philanthropic investment from Dooley LLC (to Brigham & Women's Hospital and CRS). TF has received grants from National Institute of Health Research, Michael J Fox Foundation, Innovate UK, John Black Charitable Foundation, Van Andel Research Institute and Cure Parkinson’s Trust. DPB is supported by a Wellcome Clinical Research Career Development Fellowship. RAB is an NIHR Senior Investigator (NF-SI-0616-10011) and is supported by the Wellcome Trust Stem Cell Institute (Cambridge 203151/Z/16/Z). CWG is supported by a RCUK/UKRI Research Innovation Fellowship awarded by the Medical Research Council (MR/R007446/1) and by the Cambridge Centre for Parkinson-Plus