Inflammatory bowel disease (IBD), encompassing Crohn’s disease and ulcerative colitis, is an archetypal common complex disease: patients vary markedly in prognosis and treatment response, and there is a pressing need for better biomarkers and more effective therapeutics.
I will briefly summarise our large-scale whole-exome sequencing (WES) study in IBD (~86,000 cases and 480,000 controls), which has implicated specific genes through protein-altering alleles, including protective variants in CFTR. I will then present the latest IIBDGC GWAS meta-analysis (126,000 cases and about 1.2 million controls), which has taken the number of IBD-associated loci beyond 500 and reinforces the central challenge that most common variant associations are non-coding, hindering biological interpretation.
The main focus of the talk will thus be IBDverse, a cell-type-resolved eQTL atlas generated from nearly 2.2 million single-cell transcriptomes across intestinal and blood tissues from 396 individuals, including 121 with Crohn’s disease. By mapping regulatory effects across 384 cellular contexts, we identify over 89,000 eQTLs and show that most are only detectable at the level of individual cell types, highlighting regulatory variation missed by bulk analyses. These cell-type eQTLs are more distal, enhancer-enriched, and significantly more likely to colocalise with IBD GWAS signals. Using colocalisation, we prioritise candidate effector genes at over half of known IBD loci, including MAML2 and ZMIZ1, refining mechanistic interpretation and therapeutic hypotheses. I will also compare these results to a large PBMC scRNA-seq eQTL study (Cuomo et al., 2025) to illustrate the added value of sampling disease-relevant tissues from patients with disease.
I will close by highlighting our ongoing longitudinal multiomic studies in deeply phenotyped patient cohorts, where we integrate genetic variation with repeated molecular and clinical profiling to build predictive models of inflammatory trajectories, disease progression, and treatment response, with the aim of enabling precision medicine in IBD.