Dissecting causal relationships between nonalcoholic fatty liver disease proxied by chronically elevated alanine transaminase levels and 34 extrahepatic diseases

Nonalcoholic fatty liver disease (NAFLD) is prevalent worldwide and is associated with the risk of many extrahepatic diseases. However, whether NAFLD is a risk marker or a common cause of extrahepatic diseases is unclear.We searched PubMed to identify NAFLD-related extrahepatic diseases. Genetic instrumental variables (IVs) for NAFLD surrogated by chronically elevated alanine transaminase levels and eligible extrahepatic diseases were retrieved from the corresponding genome-wide association analysis. We proposed a procedure for Mendelian randomization (MR) analysis and performed validation analyses to dissect the association between NAFLD and extrahepatic diseases. The Bonferroni method was used to correct the bias of multiple testing.In total, 34 extrahepatic diseases were included and 54 SNPs were used as IVs for NAFLD. The MR analysis gave a robust and significant (or suggestive) estimate for the association between NAFLD and 9 extrahepatic diseases: type 2 diabetes (odds ratio [OR] = 1.182, 95 % confidence interval [CI] 1.125-1.243, P = 5.40 × 10-11), cholelithiasis (OR = 1.171, 95%CI 1.083-1.266, P = 7.47 × 10-5), diabetic hypoglycemia (OR = 1.170, 95%CI 1.071-1.279, P = 5.14 × 10-4), myocardial infarction (OR = 1.122, 95%CI 1.057-1.190, P = 1.46 × 10-4), hypertension (OR = 1.060, 95%CI 1.029-1.093, P = 1.18 × 10-4), coronary artery disease (OR = 1.052, 95%CI 1.010-1.097, P = 1.58 × 10-2), heart failure (OR = 1.047, 95%CI 1.006-1.090, P = 2.44 × 10-2), dementia (OR = 0.881, 95%CI 0.806-0.962, P = 5.01 × 10-3), and pancreatic cancer (OR = 0.802, 95%CI 0.654-0.983, P = 3.32 × 10-2). Validation analyses using IVs from biopsy-confirmed and imaging-determined NAFLD reported similar results to the main analysis. For the remaining 25 outcomes, no significant or definitive association was yielded in MR analysis.Genetic evidence suggests putative causal relationships between NAFLD and a set of extrahepatic diseases, indicating that NAFLD deserves high priority in clinical practice.