A network-based systems genetics framework identifies pathobiology and drug repurposing in Parkinson’s disease

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Abstract

Parkinson’s disease (PD) is the second most prevalent neurodegenerative disorder. However, current treatments are directed at symptoms and lack ability to slow or prevent disease progression. Large-scale genome-wide association studies (GWAS) have identified numerous genomic loci associated with PD, which may guide the development of disease-modifying treatments. We presented a systems genetics approach to identify potential risk genes and repurposable drugs for PD. First, we leveraged non-coding GWAS loci effects on multiple human brain-specific quantitative trait loci (xQTLs) under the protein-protein interactome (PPI) network. We then prioritized a set of PD likely risk genes (pdRGs) by integrating five types of molecular xQTLs: expression (eQTLs), protein (pQTLs), splicing (sQTLs), methylation (meQTLs), and histone acetylation (haQTLs). We also integrated network proximity-based drug repurposing and patient electronic health record (EHR) data observations to propose potential drug candidates for PD treatments. We identified 175 pdRGs from QTL-regulated GWAS findings, such as SNCA , CTSB , LRRK2, DGKQ , CD38 and CD44 . Multi-omics data validation revealed that the identified pdRGs are likely to be druggable targets, differentially expressed in multiple cell types and impact both the parkin ubiquitin-proteasome and alpha-synuclein (a-syn) pathways. Based on the network proximity-based drug repurposing followed by EHR data validation, we identified usage of simvastatin as being significantly associated with reduced incidence of PD (fall outcome: hazard ratio (HR) = 0.91, 95% confidence interval (CI): 0.87–0.94; for dementia outcome: HR = 0.88, 95% CI: 0.86-0.89), after adjusting for 267 covariates. Our network-based systems genetics framework identifies potential risk genes and repurposable drugs for PD and other neurodegenerative diseases if broadly applied.

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