The risk factors for nonalcoholic fatty liver disease (NAFLD) have not been clearly identified. We conducted a Mendelian randomization (MR) study to explore this. Independent genetic variants strongly associated with 5 lifestyle and 9 metabolic factors were selected as instrumental variables from corresponding genome-wide association studies (GWASs). Summary-level data for NAFLD were obtained from a GWAS meta-analysis of 8434 cases and 770,180 non-cases (discovery dataset) and another GWAS meta-analysis of 1483 cases and 17,781 non-cases (replication dataset). Univariable and multivariable MR analyses were performed. There were associations with NAFLD for lifetime smoking index (odds ratio (OR) 1.59, 95% confidence interval (CI) 1.31–1.93 per SD-increase), body mass index (BMI, OR 1.33, 95% CI 1.23–1.43 per SD-increase), waist circumference (OR 1.82; 95% CI 1.48–2.24 per SD-increase), type 2 diabetes (OR 1.21, 95% CI 1.15–1.27 per unit increase in log-transformed odds), systolic blood pressure (OR 1.17; 95% CI 1.07–1.26 per 10 mmHg increase), high-density lipoprotein cholesterol (OR 0.84, 95% CI 0.77–0.90 per SD-increase), and triglycerides (OR 1.23, 95% CI 1.15–1.33 per SD-increase). The associations for type 2 diabetes, systolic blood pressure, triglycerides, but not for high-density lipoprotein cholesterol remained strong after adjusting for genetically-predicted BMI. Genetic liability to type 2 diabetes mediated 51.4% (95% CI 13.4–89.3%) of the BMI-effects on NAFLD risk. There were suggestive inverse associations of genetically-predicted alcohol, coffee, and caffeine consumption, and vigorous physical activity with NAFLD risk. This study identified several lifestyle and metabolic factors that may be causally implicated in NAFLD.

非酒精性脂肪性肝病 (NAFLD) 的危险因素尚未明确。我们进行了孟德尔随机化 (MR) 研究来探索这一点。从相应的全基因组关联研究 (GWAS) 中选择与 5 个生活方式和 9 个代谢因素密切相关的独立遗传变异作为工具变量。NAFLD 的汇总级数据来自对 8434 例病例和 770180 例非病例（发现数据集）的 GWAS 荟萃分析以及对 1483 例和 17781 例非病例（复制数据集）的另一项 GWAS 荟萃分析。进行了单变量和多变量MR分析。NAFLD 与终生吸烟指数（优势比 (OR) 1.59, 95% 置信区间 (CI) 1.31-1.93/SD 增加）、体重指数（BMI, OR 1.33, 95% CI 1.23-1.43/SD）相关- 增加），腰围（或 1。82; 95% CI 1.48-2.24 每 SD 增加），2 型糖尿病（OR 1.21，95% CI 1.15-1.27 每单位对数转换比值增加），收缩压（OR 1.17；95% CI 1.07-1.26 每 10 mmHg 增加）、高密度脂蛋白胆固醇（OR 0.84, 95% CI 0.77-0.90/SD-增加）和甘油三酯（OR 1.23, 95% CI 1.15-1.33/SD-增加）。在调整基因预测的 BMI 后，2 型糖尿病、收缩压、甘油三酯的相关性仍然很强，但与高密度脂蛋白胆固醇无关。对 2 型糖尿病的遗传易感性介导了 51.4% (95% CI 13.4–89.3%) 的 BMI 对 NAFLD 风险的影响。遗传预测的酒精、咖啡和咖啡因摄入量以及剧烈的体育活动与 NAFLD 风险之间存在暗示性的负相关。