DNA Methylation Regulates CDK5R1 and NRBP1 to Exert Effects on Alcohol Dependence: Insights From Mendelian Randomization

ABSTRACT Alcohol dependence currently lacks targeted pharmacotherapies, underscoring the urgent need for novel therapeutic targets. Existing research on disease‐associated DNA methylation changes and their gene regulatory effects remains inconsistent. To resolve this uncertainty, we applied the Mendelian randomization to elucidate causal mechanisms connecting druggable genes, epigenetic regulation and alcohol dependence development. Integrating MR, colocalization and mediation analyses, we leveraged genome‐wide association study (GWAS) (FinnGen), eQTL (eQTLGen) and methylation (GoDMC) data. We assessed causal gene‐alcohol dependence relationships, shared causal variants via colocalization and methylation‐mediated regulatory mechanisms. Our integrative analysis identified 10 drug‐targetable genes showing significant expression alterations in alcohol dependence (FDR < 0.05), with three genes (CDK5R1, CAMKK2 and NRBP1) demonstrating evidence of shared causal variants through colocalization. Epigenetic regulation was particularly evident at two methylation sites (cg07437263 and cg05102552) that indirectly influenced alcohol dependence risk by modulating CDK5R1 (63.92% mediation) and NRBP1 (95.12% mediation) expression. These findings reveal DNA methylation as a critical regulatory mechanism governing neuronal gene expression patterns in alcohol dependence pathogenesis. The strong mediation effects observed for CDK5R1 and NRBP1, coupled with their colocalization evidence, position these genes as promising candidates for both biomarker development and targeted therapeutic interventions in alcohol dependence. This investigation spotlights the regulatory function of DNA methylation on CDK5R1 and NRBP1 in alcohol dependence. It implies that CDK5R1 and NRBP1 could serve as potential clinical biomarkers or therapeutic targets for the early management of alcohol dependence.