The <scp> <i>GBA1</i> </scp> p. <scp>E427K</scp> (p. <scp>E388K</scp> ) Variant Is a Risk Factor for Synucleinopathies: A Meta‐Analysis
BACKGROUND: Variants in GBA1 are important genetic risk factors for synucleinopathies, including Parkinson's disease (PD). Although several GBA1 variants are established risk or severity modifiers, the role of the p.E427K variant remains unclear. OBJECTIVE: The aim was to determine whether the GBA1 p.E427K variant is associated with 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 resources, and large cohorts, including in-house datasets. Odds ratios (OR) were calculated for each cohort and pooled using a random-effects model. RESULTS: Across 67,221 patients and 123,832 controls, GBA1 p.E427K was associated with increased disease risk (pooled OR = 1.94, 95% confidence interval 1.33-2.84, P = 0.0007). Enzymatic data showed reduced glucocerebrosidase activity in carriers. CONCLUSIONS: The GBA1 p.E427K variant is a risk factor for synucleinopathies and should be considered in genetic studies and clinical trials. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Authors
- Farnaz Asayesh
- Алла Тимофеева
- Orly Goldstein (ORCID: https://orcid.org/0000-0001-7781-2734)
- Oury Monchi (ORCID: https://orcid.org/0000-0003-2148-5409)
- James C. Beck (ORCID: https://orcid.org/0000-0002-4884-9893)
- Sitki Cem Parlar (ORCID: https://orcid.org/0009-0003-9026-114X)
- Mandy Radefeldt
- Christine Klein (ORCID: https://orcid.org/0000-0003-2102-3431)
- Lior Greenbaum (ORCID: https://orcid.org/0000-0001-6176-0941)
- Christian Beetz (ORCID: https://orcid.org/0000-0001-7061-2895)
- Leah V. Chifamba (ORCID: https://orcid.org/0000-0003-0807-5069)
- Irina Miliukhina
- Sofya Pchelina
- Anton Emelyanov
- Y Dauvilliers
- Allison A. Dilliott (ORCID: https://orcid.org/0000-0003-3863-9304)
- Peter Bauer
- Sharon Hassin‐Baer
- Lang Liu
- Konstantin Senkevich
- Eric Yu (ORCID: https://orcid.org/0000-0003-3525-4564)
- Jamil Ahmad
- Jennifer A. Ruskey
- Cheryl Waters
- Roy N. Alcalay
- ROPAD Study Group
- Ziv Gan‐Or (ORCID: https://orcid.org/0000-0003-0332-234X)
- Nicolas Dupré
- Emma N. Somerville
- Meron Teferra
Institutions
- Montreal Neurological Institute and Hospital (CA)
- Tel Aviv University (IL)
- Columbia University Irving Medical Center (US)
- First Pavlov State Medical University of St. Petersburg (RU)
- Tel Aviv Sourasky Medical Center (IL)
- Sheba Medical Center (IL)
- McGill University Health Centre (CA)
- Centre Hospitalier Universitaire de Montpellier (FR)
- Institute of the Human Brain (RU)
- Hôpital Gui de Chauliac (FR)
- University Hospital Schleswig-Holstein (DE)
- Institut Universitaire de Gériatrie de Montréal (CA)
- Centogene (Germany) (DE)
- Parkinson's Foundation (US)
- Université Laval (CA)
- McGill University (CA)
- Université de Montréal (CA)
- Columbia University (US)
- University of Lübeck (DE)
Publication Details
- Journal
- Movement Disorders
- Published
- 2026-05-22
- DOI
- https://doi.org/10.1002/mds.70367
- Primary Topic
- Lysosomal Storage Disorders Research
- Type
- article
- Field-Weighted Citation Impact
- 0.00