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

Abstract

Inflammatory bowel disease (IBD) is a complex genetic disorder of two major phenotypes, Crohn's disease (CD) and ulcerative colitis (UC), with increased risk in Ashkenazi Jews. Twelve genome-wide linkage screens have identified multiple loci, but these screens have been of modest size and have used low-density microsatellite markers. We, therefore, performed a high-density single-nucleotide polymorphism (SNP) genome-wide linkage study of 993 IBD multiply affected pedigrees (25% Jewish ancestry) that contained 1709 IBD-affected relative pairs, including 919 CD-CD pairs and 312 UC-UC pairs. We identified a significant novel CD locus on chromosome 13p13.3 (peak logarithm of the odds (LOD) score ¼ 3.98) in all pedigrees, significant linkage evidence on chromosomes 1p35.1 (peak LOD score ¼ 3.5) and 3q29 (peak LOD score ¼ 3.19) in Jewish CD pedigrees, and suggestive loci for Jewish IBD on chromosome 10q22 (peak LOD score ¼ 2.57) and Jewish UC on chromosome 2q24 (peak LOD score ¼ 2.69). Nominal or greater linkage evidence was present for most previously designated IBD loci (IBD1-9), notably, IBD1 for CD families at chromosome 16q12.1 (peak LOD score ¼ 4.86) and IBD6 in non-Jewish UC families at chromosome 19p12 (peak LOD score ¼ 2.67). This study demonstrates the ability of high information content adequately powered SNP genome-wide linkage studies to identify loci not observed in multiple microsatellite-based studies in smaller cohorts.

Polymorphisms in E-cadherin (CDH1) result in a mis-localised cytoplasmic protein that is associated with Crohn's disease

“…Although NOD2 is the major susceptibility gene for Crohn’s disease located at IBD1, a recent genome-wide scan18 has confirmed that at least two other genes in this region are likely to be associated with Crohn’s disease 17. Here we show that CDH1 (E-cadherin), which is located within the IBD1 locus, is associated with Crohn’s disease.…”

“…E-cadherin ( CDH1 ), along with IL-4R and CD11B , was considered a likely Crohn’s disease candidate gene on chromosome 16 until NOD2 was confirmed to be associated with susceptibility to Crohn’s disease in IBD1 15 16. However, NOD2 polymorphisms do not fully explain the magnitude of genetic linkage on chromosome 16, and at least two other genes in this region are believed to be associated with Crohn’s disease 17 18. Other original chromosome 16 candidate genes, IL-4R and CD11B , were not found to be associated with Crohn’s disease;19 therefore, further susceptibility genes on chromosome 16 are expected.…”

Contributions of IBD5, IL23R, ATG16L1, and NOD2 to Crohnʼs disease risk in a population-based case-control study: Evidence of gene–gene interactions

“…This may not be surprising, given recent findings (from combined analyses of recent genomewide association studies) that there are numerous additional CD risk genes as well as several familial IBD genetic loci independent of these risk genes (i.e., IBD2, IBD4, IBD6, IBD7, IBD8, and IBD9). 45,46 Of course, there also remains the possibility that some of the observed familial risk is due to common, non-genetic risk factors shared within families, in addition to tobacco and geography.…”

Whole-genome single nucleotide polymorphism-based linkage analysis in spondyloarthritis multiplex families reveals a new susceptibility locus in 13q13

“…In the pooled analysis of the three previously published linkage analyses in SpA, conducted by Carter et al ,38 the microsatellite marker D13S218 in 13q13 achieved moderate evidence of linkage (p<0.01) with suggestive linkage (p<0.05) in the GFEGS and North American Spondylitis Consortium (NASC) datasets 20 21. Besides, the 13q13 locus has also been shown as significantly linked to Crohn's disease (CD), a chronic IBD which is frequently associated with SpA 39. In our dataset, however, comparison of the patients belonging to 13q13-linked families with the others showed no significant increase in CD frequency (table 1).…”