Brain regional and cell type-specific chromatin changes among sporadic, GBA1 variant, and APOE E4 Parkinson’s Disease

Parkinson’s disease (PD) involves myriad genetic, behavioral, and environmental factors that make the identification of effective therapeutic targets challenging. We leverage a novel, validated AI approach to identify cell type- and brain region-specific epigenomic features in 6 brain regions from 35 individuals with varying genetic risk for PD as well as clinical and pathological controls (CTRL, n=15). We observed that astrocytes of substantia nigra (SUNI) are the major regional and cellular site of differentially accessible regions (DARs) between sporadic PD (SPOR_PD+, n=15) and GBA1 mutation-carriers with PD (GBA1_PD+, n=16); Seven of these SUNI DARs not only fully separated SPOR_PD+ from GBA1_PD+ cases but could also fully separate LRRK2 mutation carriers with PD from these other two forms of PD (n=3). Molecular estimation of PD progression, which correlated with the progression of neuropathologic stage, reveals that chromatin differences between SPOR_PD+ and GBA1_PD+ increase along the predicted disease progression, with broad cell type significant differences in epigenomic profiles at predicted later stages of the disease. Having APOE 4 (n=14 cases) was shown to affect various cell types mainly in the superior and middle temporal gyrus and substantial nigra. Using a multicellular co-accessibility network analysis, we identify neuron-specific epigenomic modules that correlate with the presence of at least one APOE 4 and the increase of PD pathological and clinical phenotypes. Our results suggest that APOE 4 could contribute to PD pathogenesis through chromatin change in neural cells related to synaptic and neuronal projection processes. This study expands our understanding of genetic risk effects in Parkinson's disease and provides a blueprint framework for investigating the cellular basis of genetic risk effects in disease.