Introduction
Fibroblast growth factor 21 (FGF21) is a human metabolic hormone that is expressed in the liver, pancreas, skeletal muscle, adipocytes and brain.1 The effects of FGF21 signalling include altering of lipid metabolism and macronutrient preference.1, 2 Increased circulating FGF21 levels decrease the consumption of sweets and alcohol, but increase dietary protein intake.2 In rodents and non-human primates, increased FGF21 signalling has beneficial effects on cardiometabolic outcomes, such as reduction in fat mass and alleviation of hyperglycaemia, insulin resistance, dyslipidaemia, and cardiovascular diseases.3 Furthermore, FGF21 has also been implicated in protecting against Alzheimer’s disease,4 as well as improving lifespan.5 However, studies investigating the effect of FGF21 signalling on these clinical outcomes in humans have been inconclusive.3, 6 To prioritise the design of future clinical trials pharmacologically targeting FGF21,7 we aimed to leverage human genetic data within the Mendelian randomization paradigm to investigate the effects of higher genetically proxied circulating FGF21 levels on cardiometabolic outcomes, Alzheimer’s disease and lifespan.8