Genetic Risk Scores and Ancestry-Specific Variants Shed Light on IBD Severity
Two new studies in IBD genetics show that polygenic risk scores can predict disease severity in Danish patients, and that ancestry-specific variants in Hispanic populations reveal novel risk loci and differential effects of known genes. These findings advance precision medicine by improving risk prediction and highlighting the need for diverse genetic research.
New genetic research is advancing the ability to predict and understand inflammatory bowel disease (IBD). A study of more than 8,000 Danish patients found that higher polygenic scores for Crohn's disease and ulcerative colitis were significantly associated with a more severe disease trajectory, including increased risks for hospitalization and major surgery. Separately, the largest genetic analysis of IBD in U.S. Hispanic individuals to date, published in Gastroenterology, identified ancestry-specific risk loci associated with disease severity and outcomes.
IBD, which includes Crohn's disease and ulcerative colitis, affects between 2.4 and 3.1 million individuals in the U.S., according to the CDC. More than 400 loci have been associated with IBD.
In the Danish study, researchers included 8,267 patients — 3,732 with Crohn's disease (mean age at diagnosis, 21.8 years; 55.8% women) and 4,535 with ulcerative colitis (mean age at diagnosis, 23.3 years; 53.4% women) — from two Danish cohorts. IBD-related hospitalizations and surgeries served as primary endpoints. Higher polygenic scores (PGS) had a significant association with increased fecal calprotectin and decreased hemoglobin at diagnosis in both cohorts, and increased C-reactive protein in patients with Crohn's disease. Patients in the highest quintile of PGS had a significantly higher risk than those in the lowest quintile for hospitalization (Crohn's disease: HR = 1.81; 95% CI, 1.57-2.09; UC: HR = 1.69; 95% CI, 1.47-1.95) and major surgery (Crohn's disease: HR = 2.74; 95% CI, 2.18-3.45; UC: HR = 2.04; 95% CI, 1.55-2.69). Severe disease also had a significant association with higher PGS (Crohn's disease: OR = 1.25; 95% CI, 1.16-1.35; UC: OR = 1.33; 95% CI, 1.24-1.43). Patients in the highest quintile had a substantially higher rate of severe disease compared with those in the lowest quintile (Crohn's disease: 39.2% vs. 23.6%; UC: 34.9% vs. 20.8%).
The researchers also observed a significant association between PGS and use of various treatments, including biologics, immunomodulators and systemic corticosteroids. They noted that adjusting for disease extent mediated the severity of PGS in Crohn's disease but not in UC. “Future IBD precision medicine will most likely be based on algorithms that include many factors, such as genetics,” said the senior author. “We are gradually, step by step, getting closer to the point where we can offer more individualized care to patients.”
In the second study, researchers 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, recruited through multiple centers across the United States and Puerto Rico as part of the MiaLAtinX Consortium. Using local ancestry–aware regression, 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 associated with Crohn's disease affecting the colon rather than the small intestine.
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. Some well-known IBD risk genes, such as NOD2 and IL23R, conferred risk almost exclusively through European-derived genetic variants. Several ancestry-specific variants were linked to gene regulatory regions and influenced gene expression in immune-related tissues. Selected variants were tested 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; several ancestry-specific associations were confirmed, particularly those linked to African ancestry.
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, and treatment response.