Genetic contributions to NAFLD: leveraging shared genetics to uncover systems biology

Nonalcoholic fatty liver disease (NAFLD) affects around a quarter of the global population, paralleling worldwide increases in obesity and metabolic syndrome. NAFLD arises in the context of systemic metabolic dysfunction that concomitantly amplifies the risk of cardiovascular disease and diabetes. These interrelated conditions have long been recognized to have a heritable component, and advances using unbiased association studies followed by functional characterization have created a paradigm for unravelling the genetic architecture of these conditions. A novel perspective is to characterize the shared genetic basis of NAFLD and other related disorders. This information on shared genetic risks and their biological overlap should in future enable the development of precision medicine approaches through better patient stratification, and enable the identification of preventive and therapeutic strategies. In this Review, we discuss current knowledge of the genetic basis of NAFLD and of possible pleiotropy between NAFLD and other liver diseases as well as other related metabolic disorders. We also discuss evidence of causality in NAFLD and other related diseases and the translational significance of such evidence, and future challenges from the study of genetic pleiotropy. This Review discusses the genetics of nonalcoholic fatty liver disease (NAFLD), including evidence of shared genetic modifiers and possible pleiotropic effects between NAFLD and other liver diseases or metabolic disorders. The translational implications and future challenges are also discussed. Key points Nonalcoholic fatty liver disease (NAFLD) is a liver disorder with high heritability, and no approved pharmacotherapy to date. Although our understanding of the genetic underpinnings of NAFLD has advanced, known risk variants explain only a small fraction of heritability, suggesting the existence of ‘missing heritability’. There is evidence for shared genetic modifiers and common pathophysiological pathways that link NAFLD, other liver diseases and related metabolic disorders. Research has now progressed beyond genome-wide association studies (GWAS) to broader, causal and functional discovery via multi-trait GWAS, phenome-wide association studies (PheWAS), Mendelian randomization and functional annotation studies. The next wave of genetic studies should have substantial translational implications for both drug discovery and personalization of medicine.