Multivariate genome-wide analyses of insulin resistance phenotypes unravel novel loci and therapeutic targets for cardiometabolic health and longevity

Insulin resistance (IR) is a key risk factor for cardiometabolic diseases and premature death with unmet therapeutic needs. The limited identification of IR-associated loci hinders understanding its causal role in cardiometabolic health and longevity, impeding subsequent precise therapeutic strategies development. We applied three complementary multivariate genome-wide association study (GWAS) approaches on the homeostatic model assessment for insulin resistance, insulin resistance index, fasting insulin, and the ratio of triglycerides to high-density lipoprotein cholesterol from the MAGIC and UK Biobank (totaling N=644,158) to develop a comprehensive IR (termed ‘mvIR’) GWAS, and identified 217 independent loci for mvIR, including 24 novel loci. Multivariable Mendelian randomization (MR) analyses showed that each 1-Z-score higher mvIR was associated with higher risks of 17 cardiometabolic diseases (OR [95% CI] from 2.49 [1.75-3.53] for mild obesity-related diabetes to 1.06 [1.00-1.12] for polycystic ovary syndrome [PCOS]) and reduced likelihood of five longevity outcomes (e.g., OR of 0.64 [0.50-0.83] for 99th percentile longevity), independent of adiposity and muscle weakness indicators. Applying large-scale MR integrating GWASs, drug genomics, gene expression data, and proteomic data, we outlined 21 out of 2,644 druggable genes for IR by MR (P<1.90×10−5) and colocalization (PP.H4>0.75), and the effect direction of 14 therapeutic genes on IR aligned with their impact on diabetes, metabolic syndrome, PCOS, hypertension, cardiovascular disease, ovarian cancer, and aging phenotypes. Seven therapeutic genes (AKT1, ERBB3, FCGR1A, FGFR1, GUCY1B2, LPL, and NR1H3) encode targets for approved drugs with consistent directions of action in alleviating IR, with no significant potential side effects revealed by phenome-wide association study results. This study uncovered novel loci and therapeutic targets for IR, informing preventive strategies to promote IR-centered cardiometabolic health and longevity.