Genetics

Almramhi et al. (2023) apply a two-sample Mendelian randomization framework to disentangle whether circulating lipid fractions and statin-relevant molecular pathways exert causal effects on multiple sclerosis (MS) susceptibility and severity. Using large GWAS resources for plasma lipids, gene expression (cis-eQTLs), MS risk, and MS severity, the study separates statin biology into cholesterol-dependent mechanisms (LDL-C and cholesterol biosynthesis genes including HMGCR) and cholesterol-independent mechanisms centered on Rho GTPase signaling. The analyses provide little genetic evidence that LDL-C, triglycerides, or cholesterol-biosynthesis targets explain MS risk, but they identify a protective association between higher genetically predicted expression of the Rho GTPase gene RAC2 and MS susceptibility, alongside a risk-increasing effect of higher HDL-C on MS risk; importantly, neither lipid traits nor the tested statin-related pathways show convincing causal effects on MS severity. Collectively, the findings sharpen mechanistic hypotheses by suggesting that if statins influence MS susceptibility, it is more plausibly through immune-regulatory signaling linked to RAC2 rather than via cholesterol lowering, while also highlighting an unexpected etiologic role for HDL-C that warrants functional validation.