Integrating Genomic, eQTL, and Mendelian Randomization Analyses to Identify Microglial Drug Targets in Multiple Sclerosis

Multiple sclerosis (MS) is an autoimmune disease characterised by neuroinflammation and neurodegeneration. This study investigates genetic and immunological factors in MS, focusing on microglial regulation. We analysed differentially expressed genes using RNA sequencing from MS lesions (GSE108000) and plaques (GSE227781), validated with cis-eQTL analysis, and integrated Mendelian randomisation (MR), SMR, co-localisation, methylation, and protein-protein interaction (PPI) analyses to assess causal effects on MS risk. We identified five genes-ARHGAP25, HLA-DRB1, MERTK, MS4A6A, and SYK-linked to MS susceptibility. MR revealed that elevated levels of ARHGAP25 (OR = 1.45), HLA-DRB1 (OR = 2.24), MERTK (OR = 1.10), MS4A6A (OR = 1.15), and SYK (OR = 1.13) increased MS risk. SMR confirmed a causal link between HLA-DRB1 and MS, while co-localisation analysis showed shared variants with MS for HLA-DRB1 (100%) and SYK (97.93%). Methylation analysis highlighted 10 sites within HLA-DRB1, and PPI and DrugBank analyses revealed interactions between these genes and multiple proteins or chemicals. This study demonstrates the value of integrating genomic and eQTL data through MR to identify novel MS therapeutic targets, particularly microglial genes, offering potential new avenues for treatment.