biostudies-literatureOliveri ANIDDK NIH HHSNCI NIH HHSNIH and Department of Internal Medicine University of MichiganNIH212-221https://www.ebi.ac.uk/biostudies/studies/S-EPMC10923176biostudies-literatureUnknown56(2)Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.Nature geneticsComprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.PMC10923176R01 DK131787R01 DK106621F30 CA257292F30 CA275039R01 DK107904R01 DK128871Kuppa APrabhu PHalligan BDCushing KCDu XRaut CSpeliotes EKChen VLPant AOliveri ARebernick RJChen YBell HNfalseComprehensive genetic study of the insulin resistance marker TG:HDL-C in the UK Biobank.Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.2024-01-01T00:00:00Z2024 Feb2024-12-04T09:27:15.332Z2024-12-04T09:27:15.332ZS-EPMC109231763820012810.1038/s41588-023-01625-2