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Prediabetes is a state of glycaemic dysregulation below the diagnostic threshold of type 2 diabetes (T2D). Globally, ~352 million people have prediabetes, of which 35–50% develop full-blown diabetes within five years. T2D and its complications are costly to treat, causing considerable morbidity and early mortality. Whether prediabetes is causally related to diabetes complications is unclear. Here we report a causal inference analysis investigating the effects of prediabetes in coronary artery disease, stroke and chronic kidney disease, complemented by a systematic review of relevant observational studies. Although the observational studies suggest that prediabetes is broadly associated with diabetes complications, the causal inference analysis revealed that prediabetes is only causally related with coronary artery disease, with no evidence of causal effects on other diabetes complications. In conclusion, prediabetes likely causes coronary artery disease and its prevention is likely to be most effective if initiated prior to the onset of diabetes.

Genome-Wide Association Study (GWAS) Higher Blood pressure Arthritides Neuropsychiatric conditions Malignancies Lower Anaemias Lipidaemias Ischaemic heart disease Genetically higher central obesity Highlights Variants in HFE and TMPRSS6 are associated with higher liver iron. There is genetic evidence that higher central obesity causes higher liver iron. Liver iron variants are not organ specific and associate with multiple diseases.

Obesity and type 2 diabetes are causally related, yet there is considerable heterogeneity in the consequences of both conditions and the mechanisms of action are poorly defined. Here we show a genetic-driven approach defining two obesity profiles that convey highly concordant and discordant diabetogenic effects. We annotate and then compare association signals for these profiles across clinical and molecular phenotypic layers. Key differences are identified in a wide range of traits, including cardiovascular mortality, fat distribution, liver metabolism, blood pressure, specific lipid fractions and blood levels of proteins involved in extracellular matrix remodelling. We find marginal differences in abundance of Bacteroidetes and Firmicutes bacteria in the gut. Instrumental analyses reveal prominent causal roles for waist-to-hip ratio, blood pressure and cholesterol content of high-density lipoprotein particles in the development of diabetes in obesity. We prioritize 17 genes from the discordant signature that convey protection against type 2 diabetes in obesity, which may represent logical targets for precision medicine approaches.