The GBA1 p.E427K (p.E388K) Variant is a Risk Factor for Synucleinopathies: A Meta-Analysis
Chifamba, L. V.; Parlar, S. C.; Somerville, E. N.; Liu, L.; Yu, E.; Asayesh, F.; Ahmad, J.; Ruskey, J. A.; Waters, C.; Monchi, O.; Dauvilliers, Y.; Dupre, N.; Timofeeva, A.; Emelyanov, A.; Pchelina, S.; Miliukhina, I.; Greenbaum, L.; Hassin-Baer, S.; Goldstein, O.; Radefeldt, M.; Bauer, P.; Beetz, C.; Dilliott, A. A.; Beck, J.; Senkevich, K.; ROPAD Study Group, ; The Parkinson's Foundation PD GENEration Study, ; Klein, C.; Alcalay, R. N.; Gan-Or, Z.
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BackgroundVariants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinsons disease (PD). While several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. ObjectiveTo determine whether the GBA1 p.E427K variant is associated with risk of synucleinopathies. MethodsWe 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 resources, and large cohorts, including in-house datasets. Odds ratios (ORs) were calculated for each cohort and pooled using a random-effects model. ResultsAcross 67,484 patients and 124,079 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.87, 95% CI 1.28-2.72, P = 0.001). Enzymatic data showed reduced glucocerebrosidase activity in carriers. ConclusionsThe GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials.
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