Genome-wide association study for Crohn's disease in the Quebec Founder Population identifies multiple validated disease loci

Abstract

Genome-wide association (GWA) studies offer a powerful unbiased method for the identification of multiple susceptibility genes for complex diseases. Here we report the results of a GWA study for Crohn's disease (CD) using family trios from the Quebec Founder Population (QFP). Haplotype-based association analyses identified multiple regions associated with the disease that met the criteria for genome-wide significance, with many containing a gene whose function appears relevant to CD. A proportion of these were replicated in two independent German Caucasian samples, including the established CD loci NOD2 and IBD5. The recently described IL23R locus was also identified and replicated. For this region, multiple individuals with all major haplotypes in the QFP were sequenced and extensive fine mapping performed to identify risk and protective alleles. Several additional loci, including a region on 3p21 containing several plausible candidate genes, a region near JAKMIP1 on 4p16.1, and two larger regions on chromosome 17 were replicated. Together with previously published loci, the spectrum of CD genes identified to date involves biochemical networks that affect epithelial defense mechanisms, innate and adaptive immune response, and the repair or remodeling of tissue.haplotype ͉ complex disease ͉ IL23R C rohn's disease (CD) is a chronic inflammatory bowel disease characterized by transmural inflammatory lesions that can affect the entire gastrointestinal tract (1). The lifetime prevalence is 0.5-1% in Caucasian populations (2) and reflects the combined effects of genetic predisposition and environmental factors (3). Genetic linkage and candidate gene approaches (4-14) have contributed to the elucidation of loci influencing genetic susceptibility to CD. More recently, genome-wide association (GWA) studies (15-21) have provided further insight into the molecular pathogenesis of the disease. The top candidate genes or loci that consistently replicate include NOD2, IL23R, ATG16L1, the IBD5 region on chromosome 5q31, and a region on 5p13.1 near the PTGER4 gene. The nature of these genes suggests that the major genetic risk factors for CD are involved in the innate immune response and destruction of intracellular bacteria.It is now clear that GWA studies provide a powerful and robust new tool for the identification of the multiple susceptibility alleles involved in complex diseases. Importantly, these types of studies have the ability to identify genes that impart only moderate increases in risk (21,22). However, most studies performed to date have identified only a few top signals, and the validation of true association among signals with lower statistical significance remains a challenge. In addition, most of the GWA studies to date have been performed by using general populations, for which very large sample sizes are required for success. They have also largely relied on single-marker analysis, with genome-wide haplotype-based association analyses receiving little attention.In early 2004, we conducted a GWA study for CD...

Identification and characterization of multiple splice forms of the human interleukin-23 receptor α chain in mitogen-activated leukocytes

“…14 Subsequently, more studies have also associated this R/Q single nucleotide polymorphism with other diseases from different populations. 9,10,15,[17][18][19] Although investigating the IL23R for novel polymorphic elements, we discovered a range of novel splice variants of IL23R transcripts, greatly extending an earlier study by Zhang et al 20 from early 2006. We believe that understanding the role of these variants and how their presence is controlled will give us novel insight to the role of IL-23 in human Crohn's disease.…”

“…6,7 The importance of IL-23R in controlling innate immunity through Th17 cells may underscore why the IL23R gene also has been demonstrated to confer susceptibility to several autoimmune diseases, including psoriasis, 8,9 ankylosing spondylitis, 10 multiple sclerosis [11][12][13] and inflammatory bowel diseases (both Crohn's disease and/or ulcerative colitis). 14,15 In addition, a separate study by the Wellcome Trust Case Control Consortium and the Australo-Anglo-American Spondylitis Consortium found evidence to suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases. 16 A recent genome-wide association (GWA) study first demonstrated that IL23R is one of the genetic factors contributing to Crohn's disease.…”

Detailed genetic characterization of the interleukin-23 receptor in psoriasis

“…Detailed genetic characterization VE Garcia et al diseases including IBD (particularly adult and pediatric Crohn's disease), [16][17][18][19][20][21][22][23][24] AS, 25,26 and GO. 27 It is possible that IL23R variants also underlie susceptibility to celiac disease, 28 Graves' disease without ophthalmopathy 27 and multiple sclerosis, 28,29 although the evidence is not currently strong for celiac disease and Graves' disease without opthalmopathy and is contradictory for multiple sclerosis.…”

“…11 These results have been verified in four independent studies [12][13][14][15] and have paralleled association studies in related diseases. One of the IL23R missense SNPs implicated in psoriasis, R381Q, has also been strongly associated with several autoinflammatory phenotypes: several studies have found R381Q-mediated predisposition to adult inflammatory bowel disease (IBD), especially Crohn's disease [16][17][18][19][20][21] and pediatric Crohn's disease in individuals of European descent, [22][23][24] two sizable studies reported association of multiple IL23R SNPs with ankylosing spondylitis (AS) 25,26 and a North American study demonstrated IL23R susceptibility for Graves' ophthalmopathy (GO). 27 IL23R polymorphisms have also been studied in celiac disease with mildly significant results 28 and multiple sclerosis with conflicting results.…”

Gene-centric association mapping of chromosome 3p implicates MST1 in IBD pathogenesis

“…Testing of this SNP in our own screening and replication cohorts identifies an association signal that is equivalent in strength and that is highly correlated to rs9858213, with combined results providing overwhelming evidence that this region contains a gene for IBD (p value < 10 −12 ). A second recent GWA association study (47), also reports a significant association signal within the same region for marker rs11718165, an intronic SNP also located in BSN. The authors report several associated SNPs across a 1.2 Mb region but do not narrow down the association further.…”