The <i>GBA1</i> p.E427K (p.E388K) Variant is a Risk Factor for Synucleinopathies: A Meta-Analysis

Background Variants in GBA1 are among the most important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are well established as risk or severity modifiers, the role of the GBA1 p.E427K variant remains unclear. Objective To determine whether the GBA1 p.E427K variant is associated with increased risk of synucleinopathies. Methods We performed a meta-analysis of case-control studies reporting the frequency of GBA1 p.E427K (p.E388K) in PD and related synucleinopathies. Data were obtained from published studies, open-access genetic resources, and multiple large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. Results Across 67,484 patients with synucleinopathies and 124,079 control participants, the GBA1 p.E427K variant was associated with an increased risk of disease (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). The magnitude of effect was comparable to that reported for established GBA1 risk variants p.E365K and p.T408M (p.E326K and p.T369M). Enzymatic data demonstrated reduced glucocerebrosidase activity in PD patients with p.E427K, supporting functional relevance. Conclusions The GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered alongside other established GBA1 risk variants in genetic studies and clinical trials.