Neurology. Genetics · 2020
The SPID-GBA study: Sex distribution, Penetrance, Incidence, and Dementia in GBA-PD.
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Straniero Letizia, Asselta Rosanna, Bonvegna Salvatore, Rimoldi Valeria, Melistaccio Giada, Soldà Giulia, Aureli Massimo, Della Porta Matteo, Lucca Ugo, Di Fonzo Alessio, Zecchinelli Anna, Pezzoli Gianni, Cilia Roberto, Duga Stefano
Аннотация
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.
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.