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

TL;DR

This study combines genetic and immunological data to identify microglial genes linked to multiple sclerosis, offering new potential drug targets.

Contribution

The study integrates genomic, eQTL, and Mendelian randomization analyses to identify novel microglial drug targets in MS.

Findings

Five genes (ARHGAP25, HLA-DRB1, MERTK, MS4A6A, SYK) were linked to increased MS risk through MR analysis.

HLA-DRB1 and SYK showed strong co-localization with MS risk variants.

Methylation analysis identified 10 sites within HLA-DRB1 associated with MS.

Abstract

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.

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