CEBPB binding at rs2643219 modulates insulin sensitivity via RASGRP1–GLUT4 axis

Genome-wide association studies (GWAS) face critical limitations in resolving noncoding variants with functional impacts. Here, we introduce a function-first prioritization strategy that integrates SNP-SELEX-derived transcription factor binding profiles with genetic epidemiology. Applied to type 2 diabetes in the UK Biobank ( n = 480,000), this approach identified 305 risk SNPs—162 novel—with significantly enhanced heritability contribution, with 91 risk SNPs co-localizing at islet enhancers. CEBPB emerged as a master regulator. Focusing on a previously uncharacterized locus (rs2643219), we demonstrated allele-specific CEBPB binding at an intestinal enhancer regulating RASGRP1—a key effector for insulin-stimulated glucose uptake. CRISPR-mediated knockout of RASGRP1 in intestinal cells ablated GLUT4 translocation and impaired glucose homeostasis in mice. Trans-ethnic validation in a Chinese cohort ( n = 1718) confirmed rs2643219's clinical relevance (OR = 1.30; P = 0.023). Our strategy bridges functional genomics with pathophysiological mechanisms, establishing a blueprint for complex disease variant prioritization.