Epigenomic profile of GBA1 in Parkinson's disease

Eloise Berson; Raphael Zaghroun; Matteo Santoro; Syed Bukhari; David Seong; Chi-Hung Shu; Amalia Perna; Tomin James; Kathleen S Montine; Geidy E Serrano; Thomas G Beach; C Dirk Keene; Howard Y Chang; M Ryan Corces; Brenna Cholerton; Nima Aghaeepour; Thomas J Montine

doi:10.1016/j.parkreldis.2025.108066

Epigenomic profile of GBA1 in Parkinson's disease

Parkinsonism Relat Disord. 2025 Nov:140:108066. doi: 10.1016/j.parkreldis.2025.108066. Epub 2025 Sep 27.

Authors

Eloise Berson¹, Raphael Zaghroun², Matteo Santoro², Syed Bukhari², David Seong³, Chi-Hung Shu⁴, Amalia Perna², Tomin James⁵, Kathleen S Montine², Geidy E Serrano⁶, Thomas G Beach⁶, C Dirk Keene⁷, Howard Y Chang⁸, M Ryan Corces⁹, Brenna Cholerton¹⁰, Nima Aghaeepour¹¹, Thomas J Montine²

Affiliations

¹ Department of Pathology, Stanford University, 300 Pasteur Drive L235, Stanford, CA, 94305, USA; Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Drive H3580, Stanford, CA, 94305, USA; Department of Biomedical Data Science, Stanford University, 300 Pasteur Drive R348, Stanford, CA, USA.
² Department of Pathology, Stanford University, 300 Pasteur Drive L235, Stanford, CA, 94305, USA.
³ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Drive H3580, Stanford, CA, 94305, USA; Immunology Program, Stanford University, 240 Pasteur Drive, Stanford, CA, USA.
⁴ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Drive H3580, Stanford, CA, 94305, USA; Department of Biomedical Data Science, Stanford University, 300 Pasteur Drive R348, Stanford, CA, USA; Department of Pediatrics - Neonatal and Developmental Medicine, Stanford University, 453 Quarry Road, Stanford, CA, USA.
⁵ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Drive H3580, Stanford, CA, 94305, USA; Department of Biomedical Data Science, Stanford University, 300 Pasteur Drive R348, Stanford, CA, USA.
⁶ Department of Neuropathology, Banner Sun Health Research Institute, 10515 W. Santa Fe Drive, Sun City, AZ, 85351, USA.
⁷ Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, 1959 NE Pacific St. Box 356100., Seattle, WA, 98195, USA.
⁸ Center for Personal Dynamic Regulomes, Stanford University School of Medicine, 291 Campus Drive, Stanford, CA, 94305, USA; Howard Hughes Medical Institute, Stanford University School of Medicine, 327 Campus Drive, Stanford, CA, 94305, USA.
⁹ Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA, 94158, USA; Gladstone Institute of Data Science and Biotechnology, 1650 Owens Street, San Francisco, CA, 94158, USA; Department of Neurology, University of California San Francisco, 16514(th) ST, Suite 212, San Francisco, CA, 94518, USA.
¹⁰ Department of Pathology, Stanford University, 300 Pasteur Drive L235, Stanford, CA, 94305, USA. Electronic address: bchol@stanford.edu.
¹¹ Department of Anesthesiology, Perioperative and Pain Medicine, Stanford University, 300 Pasteur Drive H3580, Stanford, CA, 94305, USA; Department of Biomedical Data Science, Stanford University, 300 Pasteur Drive R348, Stanford, CA, USA; Immunology Program, Stanford University, 240 Pasteur Drive, Stanford, CA, USA.

PMID: 41033114
PMCID: PMC12825421 (available on 2026-09-27)
DOI: 10.1016/j.parkreldis.2025.108066

Abstract

Introduction: While genome-wide association studies have identified GBA1 as a key gene contributing to disease severity and cognitive decline in PD, its molecular effects remain poorly understood.

Methods: We used integrative bulk ATAC-seq across six brain regions from autopsied individuals with PD and varying genetic risk to characterize region- and cell type-specific molecular differences. Using Cellformer, an AI-based bulk ATAC-seq-deconvolution tool, we determined cell type-specific effects of GBA1 on PD disease progression and then validated our findings using whole transcriptome data from blood samples.

Results: Epigenomic differences between PD with ("GBA+"; n = 15) and without ("GBA-", n = 15) GBA1 variants were localized in substantia nigra. Nineteen chromatin-accessible regions strictly separated GBA+ from GBA-, including the promoter sites of key genes such as CACNA1C, EHMT1, and SLC25A48. The effect in GBA + spanned the main cell types in brain, and chromatin differences between GBA- and GBA + increased with neuropathologic progression of disease. Significant differences in the epigenomic profile in GBA+ were observed in neuronal cells (AUROC = 0.8, AUPRC = 0.8, P-value<0.0001). Validation in blood samples distinguished between GBA+ and GBA-subtypes, achieving AUROC values of 0.99. Over 5000 transcripts in blood cells distinguished GBA+ from GBA-, validating key genes and pathways from our epigenomic analysis of brain regions.

Conclusion: Our study provides novel insights into the cell type-specific epigenomic and transcriptomic landscape of GBA+ and its molecular divergence from other PD subtypes, and highlights potential therapeutic targets for this genetically defined subset of PD.

Keywords: Epigenomic; GBA; Genetics; Parkinson's disease.

MeSH terms

Aged
Disease Progression
Epigenesis, Genetic*
Epigenomics
Female
Glucosylceramidase* / genetics
Humans
Male
Middle Aged
Parkinson Disease* / genetics
Parkinson Disease* / metabolism
Parkinson Disease* / pathology
Substantia Nigra / metabolism
Substantia Nigra / pathology
beta-Glucosidase* / genetics

Substances

GBA protein, human
Glucosylceramidase
beta-Glucosidase

Abstract

MeSH terms

Substances

Grants and funding