Genome-wide analysis reveals extensive genetic overlap between childhood phenotypes and later-life type 2 diabetes

Observational studies have indicated a potential influence of childhood phenotypes on the later development of type 2 diabetes (T2D). However, the underlying biological mechanisms remain unclear. In this study, we conducted a comprehensive genome-wide analysis to investigate the shared genetic architecture and genetic loci between nine childhood phenotypes (N = 4202-620,26) and later-life T2D (N = 80,154) using genetic correlation, mendelian randomization (MR), and conjunctional false discovery rate (conjFDR) statistical frameworks. Our findings demonstrated substantial genetic correlations and pleiotropic enrichment between childhood obesity, body mass index (BMI), systolic blood pressure (SBP), diastolic blood pressure (DBP), and later-life T2D. Childhood obesity exhibited a significant association with increased later-life T2D risk through 10 mediators, 6 of which were adulthood obesity-related phenotypes. Additionally, we identified 69, 83, 3, 5, 10, 5, 3, and 7 loci shared between childhood obesity, BMI, SBP, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), apolipoprotein A-I (ApoA-I), apolipoprotein B (ApoB), and T2D at conjFDR <0.05, with the majority of these loci being novel discoveries. Overall, our study reveals extensive genetic overlap between childhood obesity-related phenotypes and T2D with concordant effect directions, shedding new light on variants and phenotypes with lifelong effects.