Uncovering Ancestry-Specific Genetic Risk in Inflammatory Bowel Disease
Summary
- Dr. Jacob McCauley and Dr. Oriana Damas are examining the genetic roots of inflammatory bowel disease in Hispanic populations.
- Most large genetic studies of IBD have focused almost exclusively on people of European ancestry. This imbalance has limited understanding of how the disease develops and behaves in other populations.
- The research team’s findings reveal that genetic ancestry plays a measurable role not only in IBD risk, but also in disease severity and clinical outcomes.
By examining the genetic roots of inflammatory bowel disease in Hispanic populations, University of Miami Miller School of Medicine researchers Jacob McCauley, Ph.D., and Oriana Damas, M.D., are helping redefine how risk, severity and treatment response may differ across genetic ancestry.
Inflammatory bowel disease (IBD), which includes Crohn’s disease and ulcerative colitis, is a chronic, immune-mediated condition shaped by a complex interplay of genetics, environment and the gut microbiome. While more than 200 genetic risk loci have been identified, most large genetic studies of IBD have focused almost exclusively on people of European ancestry. This imbalance has limited understanding of how the disease develops and behaves in other populations.
In a study published in Gastroenterology, Dr. McCauley, a professor of human genetics within the John P. Hussman Institute of Human Genomics at the Miller School, and Dr. Damas, associate professor of medicine in the Miller School’s Division of Digestive Health and Liver Diseases, joined a national group of researchers to lead the largest genetic analysis of IBD in U.S. Hispanic individuals to date. The findings reveal that genetic ancestry plays a measurable role not only in IBD risk, but also in disease severity and clinical outcomes.
A Large, Ancestry-Focused Study Design
The research team analyzed whole-genome sequencing data from approximately 7,300 self-identified Hispanic participants, including 1,660 individuals with IBD and more than 5,600 controls. Participants were recruited through multiple centers across the United States and Puerto Rico as part of the MiaLAtinX Consortium, with additional publicly available control data drawn from the Hispanic Community Health Study/Study of Latinos.
Hispanic populations are genetically admixed, typically with varying proportions of European, African and Amerindian ancestry. The research team led by Dr. McCauley, who also directs the Center for Genome Technology and Biorepository Facility, and Dr. Damas, interim director of the the Miller School’s Crohn’s and Colitis Center, used an analytical approach known as local ancestry–aware regression. Rather than treating ancestry as a single background characteristic, this method evaluates the ancestral origin of specific genetic variants at each location in the genome.
Before examining genetic variants, the researchers assessed whether genetic ancestry itself was associated with clinical features of disease. They found that higher proportions of African ancestry were linked to more severe forms of Crohn’s disease, including penetrating and perianal disease, as well as an increased likelihood of IBD-related surgery. Higher Amerindian ancestry was also associated with Crohn’s disease affecting the colon rather than the small intestine.
These findings suggest that genetic ancestry is not simply a demographic variable, but a factor tied to meaningful differences in disease presentation and outcomes.
Identifying Ancestry-Specific Genetic Risk
Using ancestry-informed, genome-wide analyses, the team identified 14 novel genetic risk loci specific to African ancestry and one genome-wide significant locus specific to Amerindian ancestry. Many of these variants were rare or absent in European populations and would not have been detected in ancestry-agnostic studies.
Importantly, the study also showed that some well-known IBD risk genes, such as NOD2 and IL23R, conferred risk almost exclusively through European-derived genetic variants. In Hispanic individuals, these variants showed little or no association with disease when inherited from African or Amerindian ancestral backgrounds.
Several ancestry-specific variants were linked to gene regulatory regions and influenced gene expression in immune-related tissues, suggesting biologically plausible mechanisms for their effects.
Replication and Broader Relevance
To validate their findings, the researchers tested selected variants in independent datasets, including Hispanic participants from the NIH’s All of Us Research Program and published studies in African American and East Asian populations. While replication was limited by sample size for some rare variants, several ancestry-specific associations were confirmed, particularly those linked to African ancestry.
These results support the idea that genetic risk for IBD is largely shared across populations, but that a subset of ancestry-specific variants may help explain differences in disease severity, complications and, potentially, treatment response.
Implications for Precision Medicine
The study’s conclusions underscore the importance of including an array of populations in genetic research. By accounting for local ancestry, researchers can uncover novel biology and refine understanding of how known risk genes operate across populations.
For patients, this work points toward a future in which genetic ancestry could inform risk prediction, monitoring for severe disease, and even therapeutic decision-making.
“The results emphasize the importance of these efforts toward learning new biology, uncovering disease mechanisms, increasing diversity in clinical trials of genetically informed therapies and identifying novel drug targets to improve care and outcomes across all populations,” the authors conclude.
Tags: biorepository, colitis, Crohn's and Colitis Center, Crohn's disease, Division of Digestive Health and Liver Diseases, Dr. Jacob McCauley, Dr. Oriana Damas, gastroenterology, genetics, IBD, inflammatory bowel disease, John P. Hussman Institute for Human Genomics, Newsroom, ulcerative colitis