Multisystem health consequences of nonalcoholic fatty liver disease: phenome-wide Mendelian randomization and disease-trajectory analyses

Introduction

The global burden of non-alcoholic fatty liver disease (NAFLD) is growing, but its subsequent health consequences have not been thoroughly examined. We performed phenome-wide Mendelian randomization and disease-trajectory analyses to comprehensively assess the health outcomes of NAFLD.

Methods

PheWAS analyses were conducted to map the associations of NAFLD with a broad range of phenotypes among 415,707 European in UK Biobank. Disease-trajectory and comorbidity analyses were applied to visualize the sequential patterns of multiple comorbidities related to the occurrence of NAFLD. The associations jointly verified by PheWAS using observational and genetically predicted NAFLD were further replicated by two-sample MR analysis using data from the FinnGen study and international consortia.

Results

PheWAS analyses on 1,172 disease outcomes revealed the associations of NAFLD with intrahepatic (e.g., chronic liver diseases and neoplasms) and extrahepatic diseases, including circulatory diseases (i.e., various cardiac diseases, hypertension and cerebrovascular diseases), metabolic diseases (i.e., hyperlipidemia and diabetes mellitus), genitourinary system diseases (i.e., renal failure), neurological disorders (i.e., dementias and Alzheimer’s disease), gastrointestinal diseases (i.e., gastritis, duodenitis and ulcerative colitis) and hematologic diseases (i.e., thrombocytopenia). Disease-trajectory and comorbidity network analyses identified 3 major extrahepatic comorbidities clusters related to NAFLD, mainly in cardiovascular, metabolic, and inflammatory diseases. Two-sample MR analyses supported the causal associations between NAFLD and the risk of several intrahepatic disorders, cardio-metabolic diseases and ascites, but found no associations with neurological diseases (i.e., dementia).

Conclusions

A prior diagnosis of NAFLD was associated with an increased risk of various extrahepatic diseases of circulatory, metabolic, genitourinary, gastrointestinal and possibly neurological systems. Three major sequential patterns of comorbidities related to NAFLD were identified, contributing to development of combination interventions targeting distinct pathways for the health promotion among NAFLD patients.