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J Crohns Colitis. 2026;20(4):jjag044
Heritability of Crohn’s disease and ulcerative colitis: A Swedish nationwide population-based twin study
Background and aims: Limited statistical power has hampered previous estimates of concordance between relatives and heritability in inflammatory bowel diseases (IBD). To examine the genetic component of Crohn’s disease and ulcerative colitis, we established the largest nationwide IBD twin cohort to date and assessed estimates of concordance and heritability.
Methods: We used the Swedish Twin Registry to identify all twins from complete pairs with known zygosity born between 1886 and 2004. The Swedish National Patient Register was used to identify all patients diagnosed with IBD. We calculated proband concordance rates and fitted a model estimating explained variance in diseases due to genetics (i.e., the heritability), environment shared between twins, and environment unique to each twin.
Results: A cohort of 111,080 twins was followed until a median age of 62.2 years, during which 964 individuals were diagnosed with IBD. The proband concordance rate for Crohn’s disease was 0.30 in monozygotic pairs and 0.02 in dizygotic pairs. The corresponding rates for ulcerative colitis were 0.15 and 0.03. After adjusting for sex and birth year, heritability was estimated to be 0.78 (95% CI: 0.68–0.87) for Crohn’s disease and 0.57 (95% CI: 0.46–0.69) for ulcerative colitis.
Conclusion: In this large population-based twin study, the heritability of Crohn’s disease was 0.78 and 0.57 for ulcerative colitis. These findings highlight the disparity between heritability estimates from twin studies and those inferred from genome-wide association studies, underscoring the need for continued exploration of the genetic basis of IBD.
Prof. Dr. Peter Hasselblatt
Deputy Director Department of Internal Medicine II, University Medical Center Freiburg, Hugstetter Str. 55, 79106 Freiburg, Germany
Genetic risk factors in inflammatory bowel disease
Inflammatory bowel disease (IBD) develops as a result of multiple factors, including diet, intestinal dysbiosis, barrier dysfunction, and environmental factors, in individuals with genetic predisposition. Although numerous genetic risk loci have been identified, the clinical relevance of genetic factors for predicting disease risk and disease course remains unclear. Monogenic forms of IBD represent an important clinical exception. These disorders typically manifest in very early childhood, often with a combined phenotype of IBD with immunodeficiency. The identification of the causative mutation allows for targeted therapies or a curative approach via allogeneic hematopoietic stem cell transplantation (Kammermeier et al., DOI: 10.1016/S2468-1253(22)00337-5). The influence of genetic factors on the risk of developing “conventional IBD” can be estimated through twin studies. Several cohort studies have demonstrated that monozygotic twins of patients with IBD have a significantly higher risk of developing IBD than dizygotic twins. The risk is particularly elevated for Crohn’s disease (CD). However, the statistical significance of these studies is limited by the relatively small number of cases included in the published twin cohorts.
A recently published Swedish twin study (Grännö et al.), to date the largest population-based study of its kind, included 111,080 twins, 964 of whom had IBD. The study showed that the concordance rate for CD was 30% in monozygotic pairs and 2% in dizygotic pairs. For ulcerative colitis (UC) the concordance rate was 15% and 3%, respectively. Taking age and sex into account, a heritability index was calculated (0–1, where an index of 1 indicates that the disease manifestation depends exclusively on genetic factors). This index was 0.78 for CD and 0.57 for UC. These data demonstrate that genetic predisposition exerts a greater influence on the risk of developing CD than on that of UC. Interestingly, the heritability risk is significantly higher than the predictions derived from genome-wide association studies (GWAS). Therefore, additional, and as yet unidentified, genetic factors appear to play an important role in the pathogenesis of IBD. However, these findings also demonstrate that genetically non-identical siblings have only a very low risk of also developing IBD.
In the context of GWAS, at least 320 susceptibility genes have been linked to the development of IBD (Liu Z et al., DOI: 10.1038/s41588-023-01384-0). Some of these genes, such as NOD2, are also associated with disease manifestation or a complicated disease course in CD. Genetic risk can be calculated using polygenic risk scores (PGS), but it was unclear to date whether such scores also correlate with disease prognosis.
In the present report by Vestergaard et al., the influence of genetic factors on IBD disease course was investigated in a Danish cohort of 3732 and 4532 patients with CD and UC, respectively. The PGS was correlated with disease outcomes. A higher PGS correlated with higher concentrations of inflammatory markers such as serum CRP or fecal calprotectin in both conditions. Additionally, patients with a higher PGS had a higher risk of IBD-related surgeries and hospitalizations. The PGS also correlated with disease severity and the need for advanced medical treatments. In CD, this association was possibly influenced by the genetically determined extent of disease manifestation.
This study thus demonstrates an association between genetic predisposition and clinical outcomes of IBD. This opens up new basic research approaches for a better understanding of the factors influencing disease severity. Furthermore, the question arises as to whether the PGS could be used for treatment decisions within the context of personalized medicine. This could help identify patients who would benefit from early escalation of therapy. Appropriate prospective studies would be required to answer this question. However, the absolute difference in clinical endpoints associated with PGS was moderate overall (the hazard ratio for surgery was only 2.74 in patients with CD and high PGS). Given the considerable costs of genetic sequencing, the benefits of genetic testing “for everyone” are likely to be limited in clinical practice for the time being and should be reserved for patients with suspected monogenic disease.