Importance:Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. Objective:To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. Design, Setting, and Participants:The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. Main Outcomes and Measures:Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. Results:Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β=4.65; 95% CI, 1.72-7.58; P=.002), E326K (β=3.42; 95% CI, 0.66-6.17; P=.02), and GBA variants combined as a single group (β=4.01; 95% CI, 1.95-6.07; P=1.5×10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β=0.38; 95% CI, 0.23-0.53; P=.01) and E326K (β=0.64; 95% CI, 0.43-0.86; P=.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P=.01) and GBA variant carriers (15 of 39 [38.5%]; P=.04) progressed to mild cognitive impairment or dementia. Conclusions and Relevance:GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.

Importance:Parkinson disease (PD) is heterogeneous in symptom manifestation and rate of progression. Identifying factors that influence disease progression could provide mechanistic insight, improve prognostic accuracy, and elucidate novel therapeutic targets. Objective:To determine whether GBA mutations and the E326K polymorphism modify PD symptom progression. Design, Setting, and Participants:The entire GBA coding region was screened for mutations and E326K in 740 patients with PD enrolled at 7 sites from the PD Cognitive Genetics Consortium. Detailed longitudinal motor and cognitive assessments were performed with patients in the on state. Main Outcomes and Measures:Linear regression was used to test for an association between GBA genotype and motor progression, with the Movement Disorder Society-sponsored version of the Unified Parkinson's Disease Rating Scale Part III (MDS-UPDRS III) score at the last assessment as the outcome and GBA genotype as the independent variable, with adjustment for levodopa equivalent dose, sex, age, disease duration, MDS-UPDRS III score at the first assessment, duration of follow-up, and site. Similar methods were used to examine the association between genotype and tremor and postural instability and gait difficulty (PIGD) scores. To examine the effect of GBA genotype on cognitive progression, patients were classified into those with conversion to mild cognitive impairment or dementia during the study (progression) and those without progression. The association between GBA genotype and progression status was then tested using logistic regression, adjusting for sex, age, disease duration, duration of follow-up, years of education, and site. Results:Of the total sample of 733 patients who underwent successful genotyping, 226 (30.8%) were women and 507 (69.2%) were men (mean [SD] age, 68.1 [8.8] years). The mean (SD) duration of follow-up was 3.0 (1.7) years. GBA mutations (β=4.65; 95% CI, 1.72-7.58; P=.002), E326K (β=3.42; 95% CI, 0.66-6.17; P=.02), and GBA variants combined as a single group (β=4.01; 95% CI, 1.95-6.07; P=1.5×10-4) were associated with a more rapid decline in MDS-UPDRS III score. Combined GBA variants (β=0.38; 95% CI, 0.23-0.53; P=.01) and E326K (β=0.64; 95% CI, 0.43-0.86; P=.002) were associated with faster progression in PIGD scores, but not in tremor scores. A significantly higher proportion of E326K carriers (10 of 21 [47.6%]; P=.01) and GBA variant carriers (15 of 39 [38.5%]; P=.04) progressed to mild cognitive impairment or dementia. Conclusions and Relevance:GBA variants predict a more rapid progression of cognitive dysfunction and motor symptoms in patients with PD, with a greater effect on PIGD than tremor. Thus, GBA variants influence the heterogeneity in symptom progression observed in PD.