Update on NAFLD genetics: from new variants to the clinic

Nonalcoholic fatty liver disease (NAFLD) is the leading cause of liver diseases in high-income countries and the burden of NAFLD is increasing at an alarming rate. The risk of developing NAFLD and related complications is highly variable among individuals and is determined by environmental and genetic factors. Genome-wide association studies have uncovered robust and reproducible associations between variations in genes such as PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13 and the natural history of NAFLD. These findings have provided compelling new insight into the biology of NAFLD and highlighted potential attractive pharmaceutical targets. More recently the development of polygenic risk scores, which have shown promising results in clinical risk prediction in other complex traits such as cardiovascular disease and breast cancer, has provided new impetus for the clinical validation of genetic variants in NAFLD risk stratification. Here we review the current knowledge on the genetic architecture of NAFLD, including gene-environment interactions, and discuss the implications and limitations of the current knowledge on NAFLD risk variants on disease pathobiology, drug discovery and risk prediction. We particularly focus on the potential clinical translation of recent genetic, discussing methodological hurdles that will have to be tackled before these discoveries are implemented in everyday practice.