Integrative analysis of Mendelian randomization and Bayesian colocalization highlights four genes with putative BMI-mediated causal pathways to diabetes

Large-scale genome-wide association studies have identified hundreds of single nucleotide polymorphisms (SNPs) that are associated with BMI and diabetes. However, there was limited data on the pathogenesis of diabetes where BMI was a mediator of the genetic causal effects on this disease. Of our particular interest is the underlying causal mechanisms of diabetes. We leveraged the summary statistics reported in two studies: UK Biobank (N = 336,473) and Genetic Investigation of ANthropometric Traits (GIANT, N = 339,224) to investigate BMI-mediated genetic causal pathways to diabetes. We first studied causal relationship between BMI and diabetes by using three Mendelian randomization methods, where a total of 76 independent BMI-associated SNPs (P <= 5×10-8) were used as instrumental variables. It was consistently shown that higher level of BMI (kg/m2) led to increased risk of diabetes. We then applied two Bayesian colocalization methods and identified shared causal SNPs of BMI and diabetes in genes TFAP2B, TCF7L2, FTO and ZC3H4. This study is the first investigation of utilizing integrative analysis of Mendelian randomization and colocalization to uncover causal relationships between genetic variants, BMI and diabetes. It highlighted putative causal pathways to diabetes mediated by BMI for four genes.