Mendelian Randomization Analysis Reveals No Causal Relationship Between Nonalcoholic Fatty Liver Disease and Severe COVID-19

BACKGROUND & AIMS: The coronavirus disease 2019 (COVID-19) pandemic has witnessed more than 4.5 million deaths as of the time of writing. Whether nonalcoholic fatty liver disease (NAFLD) increases the risk for severe COVID-19 remains unclear. We sought to address this question using 2-sample Mendelian randomization (TSMR) analysis approaches in large cohorts. METHODS: We performed large-scale TSMR analyses to examine whether there is a causal relationship between NAFLD, serum alanine aminotransferase, grade of steatosis, NAFLD Activity Score, or fibrosis stage and severe COVID-19. To maximize the power of this analysis, we performed a genome-wide meta-analysis to identify single nucleotide polymorphisms associated with NAFLD. We also examined the impact of 20 major comorbid factors of NAFLD on severe COVID-19. RESULTS: Univariate analysis of the UK Biobank data demonstrated a significant association between NAFLD and severe COVID-19 (odds ratio [OR], 3.06; P = 1.07 × 10(–6)). However, this association disappeared after demographic and comorbid factors were adjusted (OR, 1.57; P = .09). TSMR study indicated that NAFLD (OR, 0.97; P = .61), alanine aminotransferase level (OR, 1.03; P = .47), grade of steatosis (OR, 1.08; P = .41), NAFLD Activity Score (OR, 1.02; P = .39), and fibrosis stage (OR, 1.01; P = .87) were not associated with severe COVID-19. Among all NAFLD-related comorbid factors, body mass index (OR, 1.73; P = 7.65 × 10(–9)), waist circumference (OR, 1.76; P = 2.58 × 10(–5)), and hip circumference (OR, 1.33; P = 7.26 × 10(–3)) were the only ones demonstrated a causal impact on severe COVID-19. CONCLUSIONS: There is no evidence supporting that NAFLD is a causal risk factor for severe COVID-19. Previous observational associations between NAFLD and COVID-19 are likely attributed to the correlation between NAFLD and obesity.