The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD

Abstract

Objective: To provide a variant-specific estimate of incidence, penetrance, sex distribution, and association with dementia of the 4 most common Parkinson disease (PD)-associated GBA variants, we analyzed a large cohort of 4,923 Italian unrelated patients with primary degenerative parkinsonism (including 3,832 PD) enrolled in a single tertiary care center and 7,757 ethnically matched controls.

Methods: The p.E326K, p.T369M, p.N370S, and p.L444P variants were screened using an allele-specific multiplexed PCR approach. All statistical procedures were performed using R or Plink v1.07.

Results: Among the 4 analyzed variants, the p.L444P confirmed to be the most strongly associated with disease risk for PD, PD dementia (PDD), and dementia with Lewy bodies (DLB) (odds ratio [OR] for PD 15.63, 95% confidence interval [CI] = 8.04-30.37, p = 4.97*10^-16; OR for PDD 29.57, 95% CI = 14.07-62.13, p = 3.86*10^-19; OR for DLB 102.7, 95% CI = 31.38-336.1, p = 1.91*10^-14). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.80, 95% CI = 2.87-8.02, p = 2.12*10^-9; OR for DLB 12.24, 95% CI = 4.95-30.24, p = 5.71*10^-8), which, on the basis of the impact on glucocerebrosidase activity, would be expected to be mild. The 1.5-2:1 male sex bias described in sporadic PD was lost in p.T369M carriers. We also showed that PD penetrance for p.L444P could reach the 15% at age 75 years.

Conclusions: We report a large monocentric study on GBA-PD assessing mutation-specific data on the sex distribution, penetrance, incidence, and association with dementia of the 4 most frequent deleterious variants in GBA.

Figure 1. Overall and sex-specific age-related cumulative incidences of PD according to GBA genotype

(A) Vinicunca plot showing the cumulative incidence of PD in GBA-mutated patients. Each colored area represents the individual contribution of each analyzed GBA variant. (B) Cumulative incidence of PD according to genotype (heterozygosity for p.E326K, p.T369M, p.N370S, and p.L444P) and sex (the number of male and female individuals is presented in table 3). In all cases, cumulative incidence is reported as percentage (Y axis), and age reported in 20-year intervals on the X axis. PD = Parkinson disease.

Figure 2. Age-related cumulative incidence of PD, PDD, and DLB in male and female carriers of a GBA variant

Vinicunca plot showing the cumulative incidence of the GBA-associated synucleinopathies in GBA-mutated patients (A) and according to diagnosis and sex (B). In all cases, cumulative incidence is reported as percentage (Y axis), and age reported in 20-year intervals on the X axis. (C) Pie charts report the distribution of the 4 analyzed GBA variants in patients with respect to clinical diagnosis. p Values were calculated using the χ² test. DLB = dementia with Lewy body; PD only = Parkinson disease without dementia; PDD = Parkinson with dementia.