Common variants at five new loci associated with early-onset inflammatory bowel disease

Abstract

The inflammatory bowel diseases (IBD) Crohn’s disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD1. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 × 10−9), 22q12 (rs2412973, P = 1.55 × 10−9), 10q22 (rs1250550, P = 5.63 × 10−9), 2q37 (rs4676410, P = 3.64 × 10−8) and 19q13.11 (rs10500264, P = 4.26 × 10−10). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn’s disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Microbiota of De-Novo Pediatric IBD: Increased Faecalibacterium Prausnitzii and Reduced Bacterial Diversity in Crohn's But Not in Ulcerative Colitis

“…Although genetically similar ( 30 ), there are important distinctions between adult and pediatric IBD with the latter being characterized by a more extensive phenotype ( 31 ) and, at least in the case of CD, by a distinct immunophenotype ( 32 ). Environmental factors such as gastrointestinal microbial colonization may be etiological factors of relevance to this distinction; hence, it is entirely possible that pediatric IBD is defi ned by a unique microbial signature, distinct from the adult disease.…”

Loss of Prolyl Hydroxylase-1 Protects Against Colitis Through Reduced Epithelial Cell Apoptosis and Increased Barrier Function

“…Inflammatory bowel disease is a genetically heterogenous, chronic inflammatory condition with severe pathology and limited therapeutic options (10)(11)27). While the underlying causes of IBD remain largely undefined, the fundamental defect involves a loss of intestinal epithelial barrier function.…”

The pursuit of genome-wide association studies: where are we now?

“…[110][111][112] Attempts to dissect the genetic basis of early-onset or pediatric-onset IBD have also yielded some success, where several previously unreported regions for IBD have been identified. [113][114] In addition, the GWAS also found associations of many loci previously implicated for adult-onset CD and UC with early-onset IBD, thus for the first time suggesting a close relationship in the patho-physiology between early-and adult-onset IBD. 114 In addition to many newly identified genes and loci, evidence showing shared or overlapping susceptibility loci among the autoimmune diseases has also been growing.…”

“…[113][114] In addition, the GWAS also found associations of many loci previously implicated for adult-onset CD and UC with early-onset IBD, thus for the first time suggesting a close relationship in the patho-physiology between early-and adult-onset IBD. 114 In addition to many newly identified genes and loci, evidence showing shared or overlapping susceptibility loci among the autoimmune diseases has also been growing. For example, 6q23 locus was associated with both rheumatoid arthritis and systemic lupus erythematosus, whereas CD40 locus was identified for rheumatoid arthritis and multiple sclerosis.…”