Genetic Discoveries Highlight Environmental Factors as Key Drivers of Liver Disease

Abstract

Background: Over the last 50 years, genetic studies have uncovered a spectrum of rare and common alleles that confer susceptibility to both Mendelian and complex forms of liver disease. For disorders of Mendelian inheritance, identification of the causal variants has demonstrated that common environmental exposures can elicit severe liver pathogenesis in predisposed individuals. Specific environmental triggers for complex liver disorders are largely unknown; however, large-scale association studies indicate that environmental triggers are the predominant factors in driving liver pathophysiology. Key Messages: In Mendelian liver disorders, a single rare variant of major effect is often responsible for disease development. Gene-sequencing technologies have greatly facilitated the discovery of causal variants for Mendelian diseases and are increasingly utilized in molecular and clinical genetics for diagnostic and counselling purposes. By contrast, genetic susceptibility for complex liver disorders is heterogeneous, as many different genes acting on multiple distinct pathways influence disease onset and severity. Risk variants for complex liver disorders are relatively common, typically of small effect size and detected by genome-wide association studies (GWAS), which compare the genetic variation of specific loci using thousands of patients and healthy controls. Thus far, GWAS have detected dozens of unique and overlapping risk alleles for complex liver disease, but these account for less than a quarter of the overall disease liability. These observations emphasize that environmental exposures on a background of genetic predisposition are significant drivers of liver pathophysiology. Rare variants of large effect size, undetectable by GWAS, may also affect the development of complex disease on a case-to-case basis but evidence for such a scenario remains to be determined. Conclusions: Genetic technologies have identified numerous risk genes for Mendelian and complex liver disorders transforming disease recognition. For complex liver disorders, deciphering the interplay between genetic risk and environment determinants remains a significant challenge for unlocking the development of novel and personalized interventions.

The Microbiome in Primary Sclerosing Cholangitis: Current Evidence and Potential Concepts

“…The identity of such environmental risk factors is poorly known beyond the potential protective effects of smoking and coffee. [13][14][15][16][17] Among the many potential exogenous factors impacting PSC pathogenesis, 18 the gut microbiota, the collective community of all microorganisms in the gastrointestinal tract, has more recently received the major attention (►Fig. 1).…”

Novel approaches to liver disease diagnosis and modeling

“…This particularly relates to GWAS studies focused on complex diseases. Examples in the liver context are PBC (115 associations and 8 studies) and PSC (308 associations and 17 studies), in which most of the identified disease variants appeared at a very low effect size, suggesting a marginal genetic contribution in respect to other risk factors (i.e., environmental) at play (10,11).…”