The SPID- GBA Study: The Largest Monocentric Study on Sex Distribution, Penetrance, Incidence, and Association with Dementia of GBA Mutations in Parkinson's Disease

Background: Despite GBA mutations are considered the most frequent genetic risk factor for Parkinson’s disease (PD), uncertainty still exists on their impact on PD risk. This is mostly due to underpowered studies, genotyping inaccuracies, ethnic differences and underrating of mutation- age- and sex- specific effects. Methods: We studied 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. The four most common PD-associated GBA variants (p.E326K, p.T369M, p.N370S, p.L444P) were screened by multiple methods (next-generation sequencing, Sanger sequencing, allele-specific PCR). Findings: We provide for the first time an accurate mutation-specific estimate of penetrance, incidence, sex distribution, and association with dementia of p.E326K, p.T369M, p.N370S, and p.L444P variants in GBA. p.L444P confirmed to show by far the strongest association with disease risk for PD, PD dementia (PDD), and Dementia with Lewy bodies (DLB) (OR for PD 17.08, 95%CI=8.56-34.08, P=7.86*10-16; OR for PDD 32.05, 95%CI=14.89-68.99, P=7.80*10-19; OR for DLB 111.7, 95%CI=33.07-377.1, P=3.09*10-14). However, an unexpectedly high risk for dementia was conferred by p.E326K (OR for PDD 4.861 95%CI=2.90-8.13, P=1.76*10-9; OR for DLB 12.37 95%CI=4.99-30.61, P=5.37*10-8), which, purely 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 or even reverted in GBA carriers, suggesting that genetics is completely overriding the effect of sex in disease predisposition. Interpretation: Understanding the mutation-specific attributable risk is fundamental to instruct future research on disease therapy and design effective clinical trials. Age- and sex-specific penetrance for GBA variants in PD and associated phenotypes are crucial for neurologists to properly counsel patients and implement their care. Funding Statement: This work was supported by PRIN (Programmi di Ricerca Scientifica di Rilevante Interesse Nazionale, Grant n. 2017228L3J, Program coordinator SD) and by the “Fondazione Grigioni per il Morbo di Parkinson”, Milan, Italy. LS was supported by fellowships from the “Fondazione Veronesi” and “Fondazione Grigioni per il Morbo di Parkinson.” Declaration of Interests: No conflict of interest to disclose. Ethics Approval Statement: The study was approved by the “Comitato Etico Milano Area 2” the 6th of March 2018, (ID 483).