DOP46 Impact of a genetic burden on familial aggregation of inflammatory bowel disease

H.S. Lee1,2, L. Hannes1, M. Vancamelbeke3, V. Ballet4, M. Ferrante3,4, S. Vermeire3,4, I. Cleynen1

1Laboratory of Complex Genetics, Department of Human Genetics, KU Leuven, Leuven, Belgium, 2Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Republic of, 3Department Chronic Diseases Metabolism and Ageing CHROMETA, Translational Research Center for Gastrointestinal Disorders TARGID, KU Leuven, Leuven, Belgium, 4Department of Gastroenterology and Hepatology, University Hospitals Leuven, Leuven, Belgium


Family history of inflammatory bowel disease (IBD) is the strongest risk factor for IBD. There currently, however, is limited understanding of the contribution of genetic risk to familial aggregation of IBD. We aimed to evaluate the association between the IBD polygenic risk score (PRS) and familial IBD, and determine its contribution to familial IBD.


We included 54 multiple-affected families (≥3 first-degree relatives affected) of European ancestry, including 189 affected IBD patients (156 Crohn’s disease; 33 ulcerative colitis), and 133 unaffected relatives. For all individuals, Immunochip genotypes were available. Weighted PRSs with estimates derived from literature were calculated using PRSice-2.0, including clumping and different p-value thresholds (pT) to select which variants to include in the score. Explained variance (Nagelkerke pseudo-R²) was calculated across different pTs. To account for possible intra-familial correlations, the association between PRS and familial IBD was evaluated in age- and sex-adjusted generalised mixed regression models including family as random effects. Sporadic cases (n = 1768) and non-IBD controls (n = 868) with Immunochip genotypes were used for comparison.


Using pT = 0.05 for PRS calculation, we found that affected relatives had a higher PRS than unaffected relatives (p = 1.00 × 10−2), sporadic cases (p = 4.58 × 10−2), and non-IBD controls (p < 2.20 × 10−16) (Figure 1a and b). The risk of disease in families increased by 1.23-fold (95% confidence interval (CI) 1.21–1.24) for every incremental standard deviation in PRS. Individuals in the highest quartile had a 3.45 times higher risk of IBD (95% CI 1.77–6.72) than those in the lowest quartile. However, the proportion of the explained variance between affected and unaffected family members was smaller than that of sporadic IBD and non-IBD controls; and the best pT was different for familial or sporadic IBD. In familial IBD, the best-fit PRS was at pT = 6.90 × 10−3 and explained 5.3% (Figure 1c, p = 3.07 × 10−4) of variance, whereas, in sporadic IBD, the best-fit PRS was at pT = 0.08 and explained 16.7% (Figure 1d, p = 8.48 × 10−63). For sporadic IBD, a typical increase in the proportion of variance explained was seen with more liberal p-value thresholds and levelling off at ~pT = 0.1 (Figure 1d). What was striking, however, was that in familial IBD this additive genetic variance was only observed until pT = 0.01, after which explained variance dropped dramatically (Figure 1c).


Higher IBD polygenic risk increases the risk for familial IBD as it does for sporadic IBD. In sporadic IBD, the increased risk is defined by variants of all p-value levels (until ~pT = 0.1). In familial IBD, the difference between those affected or not is in the higher-effect variants (p < 0.01).