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).
Highlights
An estimated 1.4 million individuals in the United States and 2.2 million individuals in Europe suffer from inflammatory bowel disease [1] (IBD, MIM 601458, 266600, 191390), a life-long disease that occurs in the form of one of two major sub-phenotypes, Crohn disease (CD) or ulcerative colitis (UC)
The genome-wide association scans (GWS) results were not corrected for potential population substructure because (i) very low (,1023) FST values have previously been reported for different geographic regions of Germany [24], (ii) patients of panel A were all selected from the Northern part of Germany, and were geographically matched to the population-representative controls from the POPGEN biobank [25], (iii) quantile-quantile plots, which can help to identify spurious association results [26], revealed no inflation of the x2 statistics (Figure S3), and (iv) replication criteria included confirmation by family-based association tests, which are robust against population stratification [27]
We have identified nel-like 1 precursor-encoding gene (NELL1) as a novel disease gene for Crohn disease (CD), a result that was obtained in a genome-wide casecontrol association scan with 116,161 SNPs and by extensive replication in three independent samples from three distinct ethnicities
Summary
An estimated 1.4 million individuals in the United States and 2.2 million individuals in Europe suffer from inflammatory bowel disease [1] (IBD, MIM 601458, 266600, 191390), a life-long disease that occurs in the form of one of two major sub-phenotypes, Crohn disease (CD) or ulcerative colitis (UC). Familial clustering [3,4] and an increased concordance rate of IBD among monozygotic twins [5,6] are hallmarks of the genetic aetiology of IBD, a notion that is further supported by the discovery of several disease genes. This includes NOD2 [7,8,9] (IBD1), a risk haplotype in the 5q31 (IBD5) locus [10,11], DLG5 [12,13], TNFSF15 [14], ATG16L1 [15], CARD4 [16], and recently IL23R [17]. We recently performed a genomewide candidate gene analysis, using 19,779 non-synonymous SNPs, which led to the identification of a common variant (T300A) in the ATG16L1 gene as predisposing to CD [15], a finding that was later replicated by four other groups [18,19,20,21]
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