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

Genome-wide association studies have identified hundreds of single nucleotide polymorphisms (SNPs) that are associated with BMI and diabetes. However, lack of adequate data has for long time prevented investigations 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 estimated the causal effect of BMI on diabetes by using four Mendelian randomization methods, where a total of 76 independent BMI-associated SNPs (R(2) ≤ 0.001, P < 5 × 10(−8)) were used as instrumental variables. It was consistently shown that higher level of BMI (kg/m(2)) 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 utilized 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.