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Background: Observational studies have linked adiposity and especially abdominal adiposity to liver fat accumulation and non-alcoholic fatty liver disease. These traits are also associated with type 2 diabetes and coronary artery disease but the causal factor(s) underlying these associations remain unexplored., Methods: We used a multivariable Mendelian randomization study design to determine whether body mass index and waist circumference were causally associated with non-alcoholic fatty liver disease using publicly available genome-wide association study summary statistics of the UK Biobank ( n  = 461,460) and of non-alcoholic fatty liver disease (8434 cases and 770,180 control). A multivariable Mendelian randomization study design was also used to determine the respective causal contributions of waist circumference and liver fat ( n  = 32,858) to type 2 diabetes and coronary artery disease., Results: Using multivariable Mendelian randomization we show that waist circumference increase non-alcoholic fatty liver disease risk even when accounting for body mass index (odd ratio per 1-standard deviation increase = 2.35 95% CI = 1.31-4.22, p  = 4.2e-03), but body mass index does not increase non-alcoholic fatty liver disease risk when accounting for waist circumference (0.86 95% CI = 0.54-1.38, p  = 5.4e-01). In multivariable Mendelian randomization analyses accounting for liver fat, waist circumference remains strongly associated with both type 2 diabetes (3.27 95% CI = 2.89-3.69, p  = 3.8e-80) and coronary artery disease (1.66 95% CI = 1.54-1.8, p  = 3.4e-37)., Conclusions: These results identify waist circumference as a strong, independent, and causal contributor to non-alcoholic fatty liver disease, type 2 diabetes and coronary artery disease, thereby highlighting the importance of assessing body fat distribution for the prediction and prevention of cardiometabolic diseases., Competing Interests: Competing interestsThe authors declare the following competing interests: B.J.A. is a consultant for Novartis and Silence Therapeutics and has received research contracts from Pfizer, Ionis Pharmaceuticals and Silence Therapeutics. A.T. receives research funding from Johnson & Johnson Medical Companies, Medtronic, Bodynov, and GI Windows for studies on bariatric surgery and received consulting fees from Novo Nordisk and Bausch Health. All other authors declare no competing interests., (© The Author(s) 2022.)