Genome-Wide Discovery Reveals Adipose-Specific and Systemic Regulators of Insulin Resistance

Insulin resistance (IR) is a key driver of cardiometabolic disease, yet its genetic and regulatory architecture remains incompletely understood. We performed a multi-trait GWAS of fasting insulin, triglycerides, and HDL cholesterol (n ≤ 1.25 million), identifying 282 IR-associated loci, including 70 novel. Polygenic score analyses linked IR to an adverse fat distribution characterized by reduced subcutaneous and increased visceral and ectopic fat. Stratifying loci by BMI associations revealed biologically distinct variant subgroups with divergent regulatory activity during adipogenesis. Enhancer-to-gene mapping implicated 72 loci in adipose-specific regulation, including a novel LAMB1 locus, wherein knockdown enhanced adipogenesis in vitro. Coding variants in PLAUR and INPP5A implicated inflammatory and calcium signaling pathways, while Mendelian Randomization identified circulating KLK1 as a candidate causal mediator in hyperinsulinemia. Our findings refine the genetic landscape of IR, highlight adipose dysfunction as a central mechanism, and nominate new targets for mechanistic and therapeutic investigation.