By Ana Espino | Published on september 30, 2025 | 3 min read
#GallstoneDisease #GeneticLoci
#GeneticVariants
Gallstone disease, or
cholelithiasis, is an extremely common digestive condition, affecting up to
25%
of adults in some populations. Although often asymptomatic, it can lead to
serious complications such as
acute cholecystitis, biliary pancreatitis, or chronic
debilitating pain. While
metabolic and environmental factors (obesity, diet,
sedentary lifestyle) are well-established contributors, our understanding of
genetic factors remains incomplete—despite
heritability being estimated at
nearly 50%.
Faced with this reality, a major
current challenge is the identification of new genetic loci associated with
gallstone disease. The goal? To better understand the underlying biological
mechanisms and uncover potential therapeutic targets to prevent or treat this
common but often overlooked condition in public health strategies.
This is the context in which this
study was conducted: to identify
new variants associated with gallstone
disease, analyze their biological functions, and extract potential therapeutic
leads.
What if our genes were forming
stones?
Over
750,000 individuals, including
69,000 confirmed cases of gallstone disease, were included in the study. The
analysis identified
75 loci associated with gallstone disease—46 of which were
novel and had never been reported before. These loci are involved in major
biological pathways, notably cholesterol metabolism, hepatic bile acid
transport, and gallbladder motility.
Among the newly associated genes,
several present direct therapeutic interest—especially ANO1, TMEM147,
and SLC10A2, which are known for their roles in digestive function and
are already being explored as pharmacological targets in other diseases. Other
genes like ABCG8, GCKR, UGT1A1, CYP7A1, and GPBAR1
play key roles in cholesterol metabolism, bile acid synthesis, or intestinal
regulation, confirming their involvement in gallstone pathophysiology. The high
expression of these genes in hepatocytes, enterocytes, and smooth muscle cells
reinforces the idea that gallstone disease results from a combined imbalance of
hepatic, digestive, and motility-related functions.
Towards a genomics of the gallbladder?
Despite being a common digestive
disease with a significant clinical burden,
gallstone disease remains poorly
understood from a genetic standpoint. The
main challenges lie in identifying
relevant genetic loci, understanding the underlying molecular mechanisms, and
translating these insights into therapeutic strategies—especially in a context
where preventive options are virtually nonexistent.
This study aimed to
map the genetic
architecture of the disease at a genome-wide scale, integrating multi-cohort
data to identify
robust variants associated with gallstone formation. The
results expand the
known genetic repertoire, with
46 new loci identified, and
highlight potentially actionable gene targets. This opens the door to a
molecular reclassification of gallstone disease and a
targeted prevention
strategy—which currently does not exist.
Further research will help validate
the candidate genes functionally, explore their
mechanisms of action, and
develop
risk biomarkers for
early screening. It will also pave the way for
designing
targeted therapies based on the identified
biological pathways—moving
toward
predictive,
preventive, and personalized medicine applied to biliary
diseases.
Read next: The silent face of autoimmune liver diseases
About the author – Ana EspinoPhD in Immunology, specialized in Virology
