Genetics of Gallstone Disease


Gallstone disease is one of the most frequent diseases, with up to 20% of adults developing gallstones and >20% of them symptoms. The treatment of symptomatic stones and their complications by endoscopy and surgery causes high costs in health care systems. Linkage studies in families and twins demonstrated that gallstones are, in part, genetically determined. Genome‐wide association studies have identified a panel of more than 30 ‘lithogenic genes’ that confer gallstone susceptibility in humans. The largest population attributable risk is conferred by variant p.D19H of the hepatobiliary and intestinal cholesterol transporter ABCG5/G8. Deficiency of a second hepatobiliary ABC transporter, the phosphatidylcholine translocase ABCB4, causes a peculiar type of gallstone disease and chronic cholangiopathy. Other lithogenic genes affect metabolic and inflammatory pathways along the gut–liver axis. Understanding the pathobiology of gallstones might help to overcome the current invasive treatment of gallstone disease by personalised effective prevention strategies for patients at risk.

Key Concepts

  • Gallstone disease is a complex disease affected by exogenous and genetic risk factors.
  • The hepatobiliary cholesterol transporter ABCG5/G8 represents the major lithogenic gene in humans.
  • ABCB4 deficiency causes low phospholipid‐associated cholelithiasis (LPAC).
  • α1‐Antitrypsin (SERPINA1) and adiponutrin (PNPLA3) mutations do not only cause chronic liver diseases but modify gallstone disease.
  • In the future, polygenic risk scores for gallstone disease might guide prevention and non‐invasive treatment strategies.

Keywords: ABC transporters; cholelithiasis; complex disease; lithogenic gene; population attributable fraction


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Weber, Susanne N., and Lammert, Frank(Dec 2019) Genetics of Gallstone Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0028535]