Trans-ancestry meta-analysis identifies 116 gallstone disease risk loci

A trans-ancestry genome-wide association meta-analysis identified 116 genetic risk loci associated with gallstone disease, including 59 loci not reported in earlier work. The study analyzed 100,856 cases and 1,596,602 controls drawn from the UK Biobank, FinnGen, Biobank Japan and the Million Veteran Program. The researchers also reported replication of statistically compelling signals in the All of Us Research Program.

Gallstone disease is a common and costly gastrointestinal condition, but the contribution of genetic variation to susceptibility and the metabolic pathways involved remain incompletely understood. The analysis brought together large genetic and health datasets from multiple populations with different ancestries, allowing the researchers to assess gallstone disease associations across a trans-ancestry sample. It expanded the known genetic architecture of the condition through 116 risk loci, 59 of which were novel.

The team also developed a polygenic risk score using lead variants from the trans-ancestry analysis and evaluated it in the Penn Medicine BioBank. Higher scores were positively associated with liver chemistry measurements and alpha-1-antitrypsin deficiency, while lower scores were associated with total cholesterol and low-density lipoprotein levels. These associations were present in both the trans-ancestry group and the European-ancestry group. The findings describe statistical relationships in the analyzed population; they do not establish that the score predicts gallstone disease in an individual or that altering cholesterol levels would prevent the condition.

To examine relationships between the gallstone disease loci and other genetic signals, the researchers performed colocalization analyses. Comparisons between the risk loci and 44 traits yielded 321 significant colocalizations. Separate comparisons with expression quantitative trait loci from eight tissues produced 110 significant colocalizations, indicating overlap between some gallstone disease signals and gene-expression associations in the tissues examined. These analyses identify shared statistical signals but do not by themselves establish causal relationships or particular biological mechanisms.

Taken together, the results show that a large trans-ancestry meta-analysis can identify numerous genetic associations with gallstone disease and connect many of them to other traits and tissue-specific gene-expression signals. The 116 loci substantially broaden the map of gallstone disease susceptibility, while the polygenic score and colocalization results provide complementary ways to characterize the associated genetic patterns. The study’s authors concluded that the findings broaden understanding of the genetic architecture of gallstone disease.

Subject of Research: Trans-ancestry genetic analysis of gallstone disease susceptibility in large biobank populations

Article Title: Trans-ancestry genome-wide association meta-analysis of gallstone disease

Article References: Lim, J., Vujkovic, M., Levin, M. G., Lorenz, K., Voight, B. F., Zhang, D. Y., Dudek, M. F., Pahl, M. C., Pippin, J. A., Su, C., Manduchi, E., Wells, A. D., Grant, S. F. A., Abramowitz, S., Damrauer, S. M., Mukherjee, S., Yang, G., Guare, L., Setia-Verma, S., … Rader, D. J. (2026). Trans-ancestry genome-wide association meta-analysis of gallstone disease. Nature Communications. https://doi.org/10.1038/s41467-026-78644-0

Image Credits: AI Generated

DOI: 10.1038/s41467-026-78644-0

Keywords: gallstone disease, genome-wide association, trans-ancestry genetics, risk loci, polygenic risk score, colocalization, biobank research, genetic susceptibility, Trans-ancestry, genome-wide, association, meta-analysis