Nonalcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases worldwide. Observational studies have revealed various risk factors associated with NAFLD, while the causal relationships between NAFLD and clinical diseases (including obesity, diabetes and inflammation) remain unclear. In this study, based on the genome-wide association study (GWAS) data, a two-sample Mendelian randomization (MR) analysis was conducted to evaluate the causality between NAFLD and 6 clinical indicators, including body mass index (BMI), waist-to-hip ratio (WHR), C-reactive protein (CRP), fasting blood glucose (FG), fasting insulin (FI), and glycosylated hemoglobin (HbA1c). MR is based on Mendel’s law of inheritance, which uses genetic variation as a toll variable to affect the health of a population to infer causal effects in the presence of unobserved confounding. Inverse variance weighted method was the main MR method. In addition, we performed multiple steps of variable screening in the method to ensure that we were conducting the study under the MR assumption. In the MR analysis, a higher WHR (P = .0078; OR = 1.008; 95% CI, 1.002–1.013) was genetically predicted to be causally associated with an increased risk of NAFLD, while patients with higher HbA1c had a lower risk of NAFLD (P = .0437; OR = 0.44; 95% CI, 0.20–0.97). Our results showed that the genetically driven WHR and HbA1c might be potential causal factors for NAFLD, while BMI, FG, FI, and CRP were not causal factors for NAFLD, which explained the promoting role of WHR and HbA1c in the occurrence and development of NAFLD. Our finding hence revealed new insights into how nature and nurture factors underpin NAFLD, providing positive effect on the causes and prevention of this disease.