Global, regional, and national burden of gallbladder and biliary tract cancer from 1990 to 2021 and projections to 2050: a systematic analysis integrating the Global Burden of Disease 2021 and Mendelian randomization

Background: Gallbladder and biliary tract cancer (GBTC) imposes a growing global public health burden, with significant socioeconomic disparities. We assessed trends from 1990 to 2021, quantified inequalities, projected future burden, and evaluated the causal role of high body mass index (BMI) using Mendelian randomization (MR). Methods: Using Global Burden of Disease (GBD) 2021 data, we analyzed global/regional/national incidence, mortality, and disability-adjusted life years (DALYs) for GBTC. We decomposed drivers of burden changes, quantified cross-country inequalities with slope index of inequality, concentration index, projected trends to 2050 via Bayesian age–period–cohort modeling, and conducted two-sample MR to test BMI-GBTC causality. Results: Global GBTC prevalent cases increased by 142% (1990–2021), while age-standardized rates (ASRs) rose modestly (incidence EAPC = 0.97; mortality EAPC = 0.47). Burden was highest in high-socio-demographic index (SDI) regions, but low-SDI regions exhibited rising mortality and DALYs. Decomposition identified population growth as the primary burden driver across all SDI strata. Inequality analysis revealed persistent yet narrowing disparities. Projections indicated declining ASRs but rising absolute cases (+30% by 2050). MR confirmed a causal effect of elevated BMI on GBTC risk (OR = 1.0005 per unit BMI; 95% CI: 1.0000–1.0010; P = 0.043). Conclusions: GBTC burden growth is predominantly fueled by demographic forces, with worsening trends in resource-limited regions. The causal link between high BMI and GBTC underscores the need for targeted obesity interventions. Equitable prevention strategies and improved healthcare access are critical to mitigate disparities, particularly in low-SDI settings.