Lifestyle and metabolic factors for nonalcoholic fatty liver disease: Mendelian randomization study

Shuai Yuan, Jie Chen, Xue Li, Rongrong Fan, Benoit Arsenault, Dipender Gill, Edward L Giovannucci, Ju-Sheng Zheng, Susanna C Larsson

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)723-733
JournalEuropean Journal of Epidemiology
Issue number7
Early online date30 Apr 2022
Publication statusPublished - 1 Jul 2022


  • Body Mass Index
  • Cholesterol, HDL/genetics
  • Diabetes Mellitus, Type 2/epidemiology
  • Genome-Wide Association Study
  • Humans
  • Life Style
  • Mendelian Randomization Analysis
  • Non-alcoholic Fatty Liver Disease/epidemiology
  • Polymorphism, Single Nucleotide
  • Risk Factors
  • Triglycerides


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