This review aims to provide a snapshot of the actual state of knowledge on genetic variants of nuclear receptors (NR) involved in regulating important aspects of liver metabolism. It recapitulates recent evidence for the application of NR in genetic diagnosis of monogenic (“Mendelian”) liver disease and their use in clinical diagnosis. Genetic analysis of multifactorial liver diseases such as viral hepatitis or fatty liver disease identifies key players in disease predisposition and progression. Evidence from these analyses points towards a role of NR polymorphisms in common diseases, linking regulatory networks to complex and variable phenotypes. The new insights into NR variants also offer perspectives and cautionary advice for their use as handles towards diagnosis and treatment. 1. Introduction Systematically, genetic analysis with regard to disease onset and progression can be separated into pre- and post-hoc examination of monogenic or polygenic diseases. Monogenic (“Mendelian”) diseases are caused by a single gene defect and follow relatively straightforward inheritance patterns. The most prominent of these disorders are rather rare, often severe, and characterized by early onset. Genetic testing for monogenic liver disease in symptomatic patients is based on known disease-associated gene variants, thereby confirming the genetic etiology and sometimes allowing prediction of disease progression [1]. In contrast, polygenic diseases such as fatty liver disease and gallstones result from combinations of multiple gene variants and environmental factors, all of which play a role in disease initiation and progression [2]. The assessment of predisposition towards polygenic disease is based on sequence analysis of known contributory genes and construction of “polygenic risk scores” from variants of these genes [1]. Still in its infancy, personal genome information might eventually be able to predict a variety of risks associated with an individual’s lifestyle such as fatty food and alcohol consumption, as well as susceptibility to infectious diseases such as infection with hepatitis B or C virus. 2. Nuclear Receptors Nuclear receptors (NRs) are a subclass of regulatory molecules that orchestrate gene transcription in response to the presence or absence of specific ligands. Due to these functional requirements, they are characterized by the presence of a ligand-binding and a DNA-binding domain. NRs represent a central point of interaction between environment and gene regulation. They are the “hinge” connecting endogenous and environmental stimuli, that is,
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