Progression of GBA1 Gaucher-related and Parkinson’s-risk variants: A longitudinal mixed model analysis

BACKGROUND Heterozygous variants in the gene glucocerebrosidase (GBA1) causing Gaucher’s disease, a recessive lysosomal storage disorder, are involved in Parkinson’s disease (PD) pathogenesis. An association of those Gaucher-related GBA1 variants with the progression of non-motor symptoms in PD has been reported but the role of Parkinson’s-risk (PD-risk) GBA1 variants is less clear. Analysis of longitudinal changes in motor- and non-motor symptoms in carriers of the different GBA1 variants compared to non-carriers could elucidate their pathogenic relevance. OBJECTIVES To compare progression of motor- and non-motor symptoms in people with PD carrying heterozygous Gaucher-related or PD-risk GBA1 variants compared to non-carriers. METHODS We included longitudinal data of 733 individuals with typical PD. Next to non-carriers, we included 29 carriers of heterozygous Gaucher-related GBA1 variants (22 and 7 carriers of severe and mild variants, respectively) and 47 carriers of heterozygous PD-risk GBA1 variants. A two-level mixed model analysis examined interaction effects of carrying one of the three GBA1 variants (PD-risk, mild or severe) compared to non-carriers with time since diagnosis to estimate gene-variant trajectories of motor- and non-motor symptoms. RESULTS Compared to non-carriers, at nominal 5% significance level, carrying PD-risk or Gaucher-related severe variants was associated with faster cognitive decline with standardized interaction effects of 0.291 (95%CI: 0.014, 0.567, p = 0.039) and 0.614 (95%CI: 0.193, 1.036, p = 0.040), respectively. Carrying PD-risk variants was associated with faster worsening of apathy (0.380, 95%CI: 0.115, 0.645, p = 0.005), quality of sleep (0.244, 95%CI: 0.017, 0.471, p = 0.035), tremor (0.258, 95%CI: 0.001, 0.515, p = 0.050), and non-motor symptoms (MDS-UPDRS I) (0.270, 95%CI: 0.014, 0.526, p = 0.039) compared to non-carriers, while we did not observe this tendency in people with Gaucher-related mild or severe variants. The findings were not significant after Bonferroni-adjustment for 15 outcomes and 3 variants. Finally, we observed an overall slower progression in non-motor symptoms in carriers of mild variants as compared to carriers of PD-risk or severe variants. CONCLUSIONS The study suggests associations of the PD-risk variants with a more rapid disease progression compared to non-carriers and thus, if findings are confirmed in an independent cohort, advocates for a reevaluation of their pathologic relevance.