Epigenomic profile of GBA1 in Parkinson's disease

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.

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.

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.

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.