Cross-biobank genetics of gamma-glutamyl transferase in East Asians identifies loci, shared cardiometabolic comorbidities, and precision risk stratification for type 2 diabetes

Gamma-glutamyl transferase (GGT) is a clinically used biomarker of hepatobiliary injury and alcohol exposure, yet accumulating evidence links higher GGT to systemic cardiometabolic and other comorbidities. Although large-scale GWAS have defined many GGT-associated loci in European-ancestry cohorts, the genetic architecture of GGT, its cross-trait liability, and the translational utility of GGT polygenic risk remain insufficiently characterized in East Asian populations. We performed a cross-biobank genetic analysis of GGT in East Asian populations. We conducted a GWAS of circulating GGT in 46,704 Han Taiwanese participants from the CMUH Biobank and integrated GWAS summary statistics from East Asian biobanks to quantify cross-trait genetic correlations with cardiometabolic phenotypes. Putative causal effects were evaluated using univariable and BMI-adjusted multivariable Mendelian randomization (MR) analyses. Translational utility was assessed by constructing a GGT polygenic risk score (PRS) and testing its associations across the clinical phenome and in BMI-stratified time-to-event analyses of incident type 2 diabetes (T2D). In a Han Taiwanese GWAS (n = 46,704), we identified 18 genome-wide significant loci for circulating GGT, including five putative previously unreported Han Taiwanese signals at RBMS3 , APBB2 , AC091905.2 , CCDC88C , and PML after comparison with prior GGT GWAS and the GWAS Catalog. Across East Asian biobanks, GGT shared genetic liability with ALT/AST and cardiometabolic traits, including T2D, adiposity, blood pressure, and lipids. MR supported causal effects of higher GGT liability on ALT/AST, and T2D-related signals persisted after BMI-adjusted multivariable MR. A GGT PRS showed pleiotropic PheWAS associations and stratified incident T2D within BMI strata consistently. This cross-biobank study refined and extended the East Asian genetic architecture of circulating GGT and demonstrated broad shared liability with cardiometabolic traits, alongside BMI-independent causal signals for hepatic injury biomarkers and persisting T2D-related effects. These findings support the use of GGT genetics and polygenic risk for comorbidity stratification and genomics-informed risk prediction in precision medicine.