Abstract Background Despite advances in medical therapy, 1 in 10 ulcerative colitis (UC) patients still require a colectomy within 10 years of diagnosis1. We currently lack reliable predictors of disease severity, to identify patients who may benefit from earlier or more intensive therapy. To date, the DRB1*01:03 allele is the only genetic marker associated with severe UC2. In this study, we sought to validate this association and to uncover additional genetic determinants of UC severity through the largest genome-wide association study (GWAS) conducted to date. Methods Participants were recruited through the IBD BioResource (IBDBR)3 and UK IBD Genetics Consortium (UKIBDGC)4,5,6. We used kinkship analyses to identify cross-cohort duplicates and retained them in the IBDBR dataset. HLA alleles and amino-acid polymorphisms were imputed using HIBAG7 and SNP2HLA8, respectively. Only individuals of genetically inferred European ancestries were included. Severe UC was defined as patients who underwent colectomy for chronic UC or dysplasia, or received advanced therapy/immunomodulators (“flarers”). Those not meeting these criteria with ≥5 years’ follow up were classified as “fizzlers.” We identified 7,435 flarers and 2,694 fizzlers in the IBDBR, and 618 flarers and 2,694 fizzlers in the UKIBDGC. Using UC flarers as cases and UC fizzlers as controls, we performed GWAS in IBDBR using REGENIE9, adjusting for genetically inferred sex, and four genetic principal components. A fixed effects meta-analysis was performed between the IBDBR and UKIBDGC for the signals identified in the IBDBR analysis. A sensitivity analysis was conducted, correcting for disease extent, age at diagnosis, smoking at diagnosis and follow-up time to reduce potential confounding effects. Results The primary GWAS identified two loci with genome-wide significant signals (P 5x10-8). After meta-analysis, only signals within the MHC remained significant. Among them, DRB1*01:03 showed the strongest association (Table 1). After conditioning on DRB1*01:03, a second protective signal, DQA1:p.Gln175Glu, remained significant (Table 1). Sensitivity analysis indicated that these associations were not confounded by covariates (Figure 1A). We observed stronger associations while using more stringent criteria to define UC flarers, with the largest effect seen in patients requiring colectomy (Figure 1B 55(1):13-20. 2.Vestergaard MV, Nøhr AK, Allin KH, et al. HLA-DRB1*01:03 and Severe Ulcerative Colitis. JAMA. 2024;332(22). doi:10.1001/jama.2024.20429 3.Parkes M. IBD BioResource: an open-access platform of 25 000 patients to accelerate research in Crohn’s and Colitis. Gut. 2019;68(9):1537-1540. 4.Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661-678. 5.Genome-wide association study of ulcerative colitis identifies three new susceptibility loci, including the HNF4A region. Nature Genetics. 2009;41(12):1330-1334. 6.de Lange KM, Moutsianas L, Lee JC, et al. Genome-wide association study implicates immune activation of multiple integrin genes in inflammatory bowel disease. Nature genetics. 2017;49(2). doi:10.1038/ng.3760 7.Zheng X, Shen J, Cox C, et al. HIBAG—HLA genotype imputation with attribute bagging. The Pharmacogenomics Journal. 2013;14(2):192-200. 8.Jia X, Han B, Onengut-Gumuscu S, et al. Imputing Amino Acid Polymorphisms in Human Leukocyte Antigens. PLOS ONE. 2013;8(6):e64683. 9.Mbatchou J, Barnard L, Backman J, et al. Computationally efficient whole-genome regression for quantitative and binary traits. Nature Genetics. 2021;53(7):1097-1103. Conflict of interest: Zhang, Qian: No conflict of interest Parkes, Miles: Grant: Gilead, Pfizer, AstraZeneca, Galapagos, Lilly, Takeda Anderson, Carl: Personal Fees: Carl Anderson (CAA) has received consultancy or speaker fees from Genomics plc, BridgeBio Ltd and Glaxo Smith Kline. Fachal, Laura: I have no conflicts of interest Lee, James: Grant: GSK Personal Fees: Abbie, C4X Discovery, PredictImmune, Falk
Zhang et al. (2026) studied this question.