Reactive astrocyte-related pathogenic genes in Parkinson's disease: A multi-omics Mendelian randomization study

Background Reactive astrocytes are one of the pathological features of Parkinson's disease (PD) and are associated with neuroinflammation and neuronal damage. Objective To explore the causal relationship between reactive astrocyte-related genes and PD through the summary data-based Mendelian randomization (SMR). Methods We combined these reactive astrocyte-related Quantitative Trait Loci (QTLs) data with PD genome-wide association study (GWAS) statistics. Using SMR, we explored causal links between gene expression, methylation and protein levels (pQTL) with PD, which were validated through colocalization analysis, replication cohorts and substantia nigra tissue data. The study also explored the causal relationship between DNA methylation and gene expression. Results SMR analysis identified 95 mQTLs (corresponding to 44 genes), 9 eQTLs, and 7 pQTLs nominally associated with PD (P-SMR_multi < 0.05 & P-SMR < 0.05, and P-HEIDI > 0.01). There was still a significant causal association between MAPK1 expression and Parkinson's disease risk after FDR correction (OR = 2.085, 95%CI = 1.463 to 2.972, P-HEIDI = 0.225, P-SMR FDR = 0.013), supported by strong colocalization (PPH4 = 0.987). Similarly, there was a significant association between corrected CTSB protein levels and Parkinson's disease risk (OR = 0.855, 95%CI = 0.791 to 0.925, P-HEIDI = 0.076, P-SMR FDR = 0.028). The methylation and expression of CLEC3B and PLAU were both nominally associated with the risk of PD. Further analysis revealed that there was also a causal relationship between their methylation and expression. Conclusions We identified the MAPK1 gene as a potential causative gene for PD. Its high expression was robustly causally associated with an increased risk of PD and was supported by strong colocalization evidence.