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

Abstract

Variants in the <i>GBA1</i> 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' <i>GBA1</i> variants on PD course is less clear. In this study, we report the effect of <i>GBA1</i> variants in incident PD patients with long-term follow-up. 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' <i>GBA1</i> variants and carriers of pathogenic <i>GBA1</i> 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 <i>GBA1</i> variants on these outcome measures. <i>GBA1</i> variants were identified in 14.4% of patients. Pathogenic and 'non-pathogenic' <i>GBA1</i> variants were associated with the accelerated development of dementia and a more aggressive motor course. Pathogenic <i>GBA1</i> variants were associated with earlier mortality in comparison with non-carriers, independent of the development of dementia. <i>GBA1</i> variants, including those not associated with Gaucher disease, are common in PD and result in a more aggressive disease course.