Systematic Association Mapping Identifies NELL1 as a Novel IBD Disease Gene

Abstract

Crohn disease (CD), a sub-entity of inflammatory bowel disease (IBD), is a complex polygenic disorder. Although recent studies have successfully identified CD-associated genetic variants, these susceptibility loci explain only a fraction of the heritability of the disease. Here, we report on a multi-stage genome-wide scan of 393 German CD cases and 399 controls. Among the 116,161 single-nucleotide polymorphisms tested, an association with the known CD susceptibility gene NOD2, the 5q31 haplotype, and the recently reported CD locus at 5p13.1 was confirmed. In addition, SNP rs1793004 in the gene encoding nel-like 1 precursor (NELL1, chromosome 11p15.1) showed a consistent disease-association in independent German population- and family-based samples (942 cases, 1082 controls, 375 trios). Subsequent fine mapping and replication in an independent sample of 454 French/Canadian CD trios supported the authenticity of the NELL1 association. Further confirmation in a large German ulcerative colitis (UC) sample indicated that NELL1 is a ubiquitous IBD susceptibility locus (combined p<10−6; OR = 1.66, 95% CI: 1.30–2.11). The novel 5p13.1 locus was also replicated in the French/Canadian sample and in an independent UK CD patient panel (453 cases, 521 controls, combined p<10−6 for SNP rs1992660). Several associations were replicated in at least one independent sample, point to an involvement of ITGB6 (upstream), GRM8 (downstream), OR5V1 (downstream), PPP3R2 (downstream), NM_152575 (upstream) and HNF4G (intron).

No association between TNFSF15 and IL23R with ulcerative colitis in Koreans

“…[1][2][3][4] The incidence of IBD is relatively higher in Caucasian than in Asian populations; however, the incidence in Asia is increasing. 5,6 Of the two types of IBD, the genetic contribution to disease risk has been documented more extensively and clearly for CD [7][8][9][10][11][12][13][14][15][16][17] than for UC. [18][19][20][21] So far, linkage and genome-wide association studies have identified more than 30 CD-susceptibility loci in Caucasian populations.…”

Microbiota regulate intestinal epithelial gene expression by suppressing the transcription factor Hepatocyte nuclear factor 4 alpha

“…HNF4A is predicted to bind a majority of IBD-linked CRRs and to regulate IBD-linked genes (Haberman et al 2014;Meddens et al 2016). Similarly, genetic variants near human HNF4G have been associated with obesity and CD (Franke et al 2007;Berndt et al 2013). Importantly, these diverse roles for HNF4 TFs in host physiology have only been studied in animals colonized with microbiota.…”

An SNP linkage scan identifies significant Crohn's disease loci on chromosomes 13q13.3 and, in Jewish families, on 1p35.2 and 3q29

“…Conversely, we did not observe any CD linkage peaks among chromosomal segments that correspond to any of the multiple, highly significant novel associations observed among recent CD genomewide association studies with the exception of NOD2. 33,[35][36][37][38] Notably, for the three most well-replicated associations after NOD2-the IBD5 risk haplotype, IL23R and ATG16L1-the established risk haplotypes or missense variants associated are common in the population and thus the inheritance of risk alleles may frequently come from different founders within a given pedigree weakening potential linkage signals. 33,34 The findings of the present study support the concept that genome-wide linkage and association studies represent complementary approaches to gene identification.…”