Epidemiology and population genetics suggest that Parkinson’s disease (PD), Lewy Body Dementia (LBD) and related synucleinopathies, results from a complex interaction between genetic risk, aging, and environmental factors. Although genome wide association studies (GWAS) have identified numerous sequence variants associated with the risk to develop neurodegenerative diseases, a comprehensive mechanistic understanding how specific risk variants functionally contribute to the disease’s pathology remains elusive. Genome-scale epigenetic studies find the enrichment of GWAS variants in gene regulatory elements (GREs), suggesting that non-coding risk variants can affect disease pathogenesis by altering in the transcription of disease genes. To identify causal PD-GWAS variants within GREs, we integrated GWAS data with epigenetic information. Employing a novel CRISPR/Cas9-based platform in human pluripotent stem cells (hPSCs) to dissect the function GREs, we identified a GWAS-nominated enhancer that cis-regulates the expression of GPMNB. GPNMB, preferentially expressed in microglia in the CNS, is upregulation in many neurodegenerative disorders including PD, Alzheimer’s diseases (AD) and related dementias (ADRD). Our pilot studies using CRISPR/Cas9 mediated gain- and loss-of-function analysis in hPSC-derived microglia suggest a critical role of GPNMB in coordinating the neurodegeneration-associated neuroinflammatory response. We therefore hypothesize that cis- acting effects of GWAS risk variants lead to increased GPMNB expression in microglia, which enhances an inflammatory response that actively contributes to the neuronal damage in PD, LBD and related synucleinopathies. The goal of this proposal is to determine the role of GPNMB in the pathogenesis of PD, LBD and related synucleinopathies. Specifically, we will combine GWAS information and cell-type specific epigenetic data with CRISPR/Cas9 genome editing to identify the causal GWAS-risk variant and molecularly define the regulation of GPNMB. Furthermore, employing molecular and cell biological tools, we will perform gain- and loss-of-function analysis to determine GPNMB’s role in coordinating neuroinflammation and its contribution to the neurodegeneration associated with -synuclein pathology. Finally, we will confirm the relevance of our in vitro findings in a more disease-relevant context by utilizing human-mouse microglia brain chimeras and primary brain tissue samples obtained from patients diagnosed with PD, LBD, and related synucleinopathies. Our findings will provide critical insights on the role of GPNMB as common feature in the pathogenesis of PD, LBD and related synucleinopathies. Furthermore, this work will establish an experimental platform for advancing from genetic association to causal biology. The understanding of how genetic factors affecting non-neuronal cells contribute to neurodegenerative diseases is pivotal, as it offers a potential avenue for targeting these non- cell autonomous...