Abstract Inflammatory bowel diseases (IBD), principally Crohn’s disease (CD) and ulcerative colitis (UC), are common chronic disorders involving inflammation and often progressive tissue damage. Genome-wide association studies have mapped many risk signals, but the causal variants, effector genes and relevant cellular contexts remain difficult to resolve, limiting mechanistic interpretation and therapeutic translation. Here we performed a multi-ancestry GWAS meta-analysis of 125,992 individuals with IBD and more than 1.2 million controls, identifying 619 independent association signals (374 novel) at 420 IBD regions that account for 77–80% of SNP-based heritability. Fine-mapping resolved 81 high-confidence variants, 41 not previously reported. Although most signals were shared between CD and UC, 39% showed IBD subtype specificity, with UC signals showing stronger enrichment in functional annotations from intestinal epithelial, secretory and enteroendocrine cells, and CD showing stronger genetic correlations with circulating inflammatory biomarkers, including C-reactive protein and glycoprotein acetylation. Latent causal modelling supported a causal effect of decreased high-density lipoprotein on CD risk. By integrating bulk and single-cell eQTL and pQTL resources using colocalisation and Mendelian randomisation, together with coding-variant evidence from exome sequencing, we prioritised 664 candidate effector genes across 341 signals, including 390 newly implicated IBD genes, revealing new biological mechanisms and candidate therapeutic targets supported by human genetics.
Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition)
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ObjectiveThe purpose of this study was to investigate the impact of obesity on disease activity and disease outcome in patients with inflammatory bowel disease.Patients and methodsThe impact of obesity on inflammatory bowel disease disease activity and outcome was retrospectively assessed in 3075 patients enrolled in the prospective nation‐wide Swiss inflammatory bowel disease cohort between July 2006 and September 2018. Baseline characteristics, disease activity and disease course in 325 obese inflammatory bowel disease patients (body mass index ≥30 kg/m2) were compared to 1725 normal weight inflammatory bowel disease individuals (body mass index 18.5‐24.9).ResultsAmong 3075 patients in the prospective Swiss inflammatory bowel disease cohort, 325 patients (10.6%) were obese, namely, 194 Crohn’s disease patients, 131 ulcerative colitis, and inflammatory bowel disease‐unclassified patients. Disease activity scores were elevated in obese Crohn’s disease (Crohn’s Disease Activity Index 33 vs 20, p = 0.001), but not ulcerative colitis patients. Obese Crohn’s disease, but not ulcerative colitis patients were less likely to be in remission based on a Crohn’s Disease Activity Index less than 100 and a calprotectin less than 100 ug/g. In a multivariate regression model, obesity was negatively associated with disease remission in Crohn’s disease (odds ratio 0.610, 95% confidence interval 0.402–0.926, p = 0.020), but not ulcerative colitis. Increased soft stool frequency was observed in both obese Crohn’s disease and ulcerative colitis patients. Adjusted Cox regression models revealed increased risk of complicated disease course in obese Crohn’s disease patients (hazard ratio 1.197, 95% confidence interval 1.046–1.370, p = 0.009). No association between obesity and disease progression, index treatment failure was seen neither in Crohn’s disease nor ulcerative colitis.ConclusionObesity is associated with decreased rates of disease remission and increased risk of complicated disease course in Crohn’s disease over a six‐year follow‐up period. No effects were seen on disease progression and index treatment failure neither in Crohn’s disease nor ulcerative colitis.