Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease

Ceballos, F.; Boekstegers, F.; Scherer, D.; Barahona Ponce, C.; Marcelain, K.; Garate-Calderon, V.; Rojas, A.; Munoz, C.; Retamales, J.; de Toro, G.; Vera Kortmann, A.; Barajas, O.; Rivera, M. T.; Cortes, A.; Loader, D.; Saavedra, J.; Gutierrez, L.; Ortega, A.; Bertran, M. E.; Bartolotti, L.; Gabler, F.; Campos, M.; Alvarado, J.; Moisan, F.; Spencer, L.; Nervi, B.; Carvajal-Hausdorf, D.; Losada, H.; Almau, M.; Fernandez, P.; Olloquequi, J.; Rothhammer, F.; Lorenzo Bermejo, J.

doi:10.1101/2024.04.22.590517

Home/Archive/bioRxiv

bioRxiv · 10.1101/2024.04.22.590517

Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease

View original source ↗Export metadata ↓

Abstract

Latin Americans have a rich genetic make-up that translates into heterogeneous fractions of the autosomal genome in runs of homozygosity (FROH), and heterogeneous types and proportions of indigenous American ancestry. While autozygosity has been linked to several human diseases, very little is known about the relationship between inbreeding, genetic ancestry and cancer risk in Latin Americans. Chile has one of the highest incidences of gallbladder cancer (GBC) in the world, and here we investigated the association between inbreeding, GBC, gallstone disease (GSD) and body mass index (BMI) in 4029 genetically admixed Chileans. We calculated individual FROH above 1.5 Mb and weighted polygenic risk scores for GSD, and applied multiple logistic regression to assess the association between homozygosity and GBC risk. We found that homozygosity was due to a heterogeneous mixture of genetic drift and consanguinity in the study population. Although we found no association between homozygosity and overall GBC risk, we detected interactions between FROH and sex, age, and genetic risk of GSD on GBC risk. Specifically, the increase in GBC risk per 1% FROH was 19% in men (P-value = 0.002), 30% in those under 60 years of age (P-value = 0.001), and 12% in those with a genetic risk of GSD above the median (P-value = 0.01). The present study highlights the complex interplay between inbreeding, genetic ancestry and genetic risk of GSD in the development of GBC. The applied methodology and our findings underscore the importance of considering the population-specific genetic architecture, along with sex- and age specific-effects, when investigating the genetic basis of complex traits in Latin Americans.

Explore related subjects

genetics Preprint

Keep this discovery

Explore connections, maps & timelines

BibTeX RIS

Ceballos, F., Boekstegers, F., Scherer, D., Barahona Ponce, C., Marcelain, K., Garate-Calderon, V., Rojas, A., Munoz, C., Retamales, J., de Toro, G., Vera Kortmann, A., Barajas, O., Rivera, M. T., Cortes, A., Loader, D., Saavedra, J., Gutierrez, L., Ortega, A., Bertran, M. E., Bartolotti, L., Gabler, F., Campos, M., Alvarado, J., Moisan, F., Spencer, L., Nervi, B., Carvajal-Hausdorf, D., Losada, H., Almau, M., Fernandez, P., Olloquequi, J., Rothhammer, F., Lorenzo Bermejo, J.. 2024-04-26. Inbreeding and gallbladder cancer risk: Homozygosity associations adjusted for indigenous American ancestry, BMI and genetic risk of gallstone disease. https://doi.org/10.1101/2024.04.22.590517

Cite the original work for its findings. Save a collection to share your selection of sources.

KEEP EXPLORING

Related preprints

bioRxiv2026

Large language model-based bibliometric evaluation of population descriptors in human genetics

As the use of population descriptors such as race, ethnicity, and ancestry have become increasingly common in modern genetics research, there have been growing calls to critically examine their use. Most notably, in 2023, the National Academies of Science, Engineering, and Medicine (NASEM) published a report titled Using Population Descriptors in Genetics and Genomics Research: A New Framework for an Evolving Field, which included eight specific and actionable recommendations for researchers to implement the ethical and accurate use of population descriptors in genetic research. Here, we use the 2023 NASEM report as a benchmark to analyze the use of population descriptors in genome-wide association studies (GWAS). We develop a general toolkit for large language model-based bibliometrics, operationalize the report's recommendations into an evaluation framework, and apply this framework to evaluate all 4,007 papers from the GWAS Catalog published between 2007 and 2025 with full text available on PubMedCentral. We find significant improvements in adherence to NASEM report recommendations over time. However, most improvements predate the publication of the NASEM report itself, suggesting the report functioned primarily as a synthesis of existing best practices rather than a catalyst for change. We conclude by highlighting opportunities for growth in the field of human genetics.

genetics↗

bioRxiv2026

Mitigating biases of rescaling in forward-in-time population genetic simulations

Forward-in-time population genetic simulations are widely used in evolutionary analyses, but simulating large populations and long genomic regions remains computationally demanding. To reduce this cost, parameter rescaling is widely employed, in which the original evolutionary process is approximated by one with a smaller population size and fewer generations. Recently, several studies using the SLiM simulator have raised concerns about the accuracy of this rescaling approach. In this study, we show that many of the biases reported in these studies can be mitigated by using a different simulation algorithm. These results reveal that the accuracy of parameter rescaling depends on how well the simulation algorithm preserves diffusion-limit properties under rescaling.

genetics↗

bioRxiv2026

OPA1 controls mitochondrial dysfunction-driven liver fibrosis in MASLD

Progressive hepatic fibrosis is the principal determinant of morbidity and mortality in metabolic dysfunction-associated steatotic liver disease and steatohepatitis (MASLD/MASH). Mitochondrial dysfunction is a hallmark of MASH, and the release of mitochondrial damage-associated molecular patterns (mito-DAMPs) from injured hepatocytes can promote fibrosis. However, how mitochondrial dynamics and quality control shape the fibrotic response in MASLD/MASH remains unclear. Here, through large-scale genomic analyses of mitochondrial genes governing mitophagy, fusion and fission in human MASLD, with a power-equivalent sample size of approximately 700,000 individuals, we identify a strong association between hepatic fibrosis and the mitochondrial fusion factor dynamin-like GTPase optic atrophy 1 (OPA1). OPA1 transcripts and protein abundance in the liver epithelium were progressively dysregulated with advancing fibrosis. In mice, hepatocyte-specific OPA1 loss alone was sufficient to induce hepatic stellate cell activation and fibrosis in zone 3, promoted the release of mito-DAMPs into the circulation and exacerbated fibrosis in experimental MASH. These findings identify OPA1 as a central regulator of the hepatic fibrotic response and connect defective mitochondrial homeostasis to mito-DAMP release, hepatic stellate cell activation and fibrosis in MASLD.

genetics↗