Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Abstract

Several new risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further we have combined the data from three studies (a total of 3,230 cases and 4,829 controls) and performed replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 new loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1, and ITLN1. The expanded molecular understanding of the basis of disease offers promise for informed therapeutic development. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptThe first genome-wide association studies (GWAS) have identified many common variants associated with complex diseases, and have rapidly expanded our knowledge of the genetic architecture of these traits. Progress in Crohn's disease (CD), a common idiopathic inflammatory bowel disease (IBD) with high heritability (λ s ∼ 20-35), has been especially striking, with recent GWAS publications increasing the number of confirmed associated loci from two to more than ten 1 . The results have identified new pathogenic mechanisms of IBD and promise to advance fundamentally our understanding of CD biology. These recent discoveries highlight, for instance, the key importance of autophagy and innate immunity 2-5 as determinants of the dysregulated host-bacterial interactions implicated in disease pathogenesis. Furthermore, genetic associations have been shown to be shared between CD and other auto-inflammatory conditions -for example, IL23R variants 6 are also associated with psoriasis 7 and ankylosing spondylitis 8 , and PTPN2 variants with type 1 diabetes 3,5 . As in other complex diseases, restricted sample sizes have resulted in early CD studies focusing on only the strongest effects, which turn out to explain only a fraction of the heritability of disease.We recently published three separate GWA scans for CD in European-derived populationsthe details of which are shown in Table 1 4,5,9 . Motivated by the need for larger datasets to improve power to detect loci of modest effect, we carried out a genome-wide meta-analysis from our three CD scans. These analyses, together with a replication study in an equivalently sized, independent panel, have enabled us to identify at genome-wide levels of significance 21 novel Crohn's disease susceptibility genes and loci. This brings the total number of independent loci conclusively associated with Crohn's disease to more than 30 and provides unprecedented insight into both CD pathogenesis as well as the general genetic architecture of a multifactorial disease. Results Meta-analysis of three genome-wide association scansThe combined GWAS study samples (Table 1) consisted of 3,230 cases and 4,829 controls, all of European descent. While the individual scans did identify new risk factors, they were only well-powered to discover common alleles with odds-ratios (ORs) a...

Genome‐wide association studies of multiple sclerosis

“…Notably, in some cases the allele associated with increased MS risk is associated with decreased risk to another autoimmune disease. One example is rs744166 (located in an intron of the STAT3 gene on chromosome 17): the G allele is associated with increased risk in MS38 and decreased risk in Crohn's disease 71…”

Association of the AFF3 gene and IL2/IL21 gene region with juvenile idiopathic arthritis

“…For example in PTPN22, the minor allele of the R620W SNP is associated with greater risk of developing RA, JIA, T1D and SLE but is protective for Crohn's disease. 24,25 There is also emerging data suggesting that one of the associated SNPs at the IL2RA locus confers differing risk and protective effects for T1D and multiple sclerosis. 26,27 JIA is a phenotypically heterogeneous disease and can be classified into more clinically homogeneous diseases using the ILAR classification criteria (Supplementary Table 1).…”

ANKRD55 and DHCR7 are novel multiple sclerosis risk loci

“…6 An intronic SNP, rs2301436 in FGFR10P, which flanks the CCR6 gene locus was first identified in Crohn's disease (CD). 8 More recently, rs3093023 in the promoter area of CCR6 at 1.9 kb from the transcription initiation site emerged as risk factor for RA in populations of European ancestry, while rs3093024, also located in the CCR6 promoter at 1.5 kb upstream from rs3093023 and in perfect linkage disequilibrium (LD) with it (D 0 ¼ 1, r 2 ¼ 1) in the European population, was identified as RA risk factor in the Japanese population. 6,9 Further evidence for the generalized involvement of the CCR6 gene region in autoimmune disease risk comes from two independent GWAS on vitiligo each of which identified strongly associated SNPs located 30 --175 kb upstream from CCR6.…”

“…20,23 The PRDM1 gene region was identified as susceptibility locus for CD, UC, SLE and RA through meta-analyses of GWAS coupled to replication exercises in independent sample sets. 8,22,24,25 The most strongly associated SNPs identified in the CD and UC studies, rs7746082 and rs6911490, respectively, are in partial LD (D 0 ¼ 0.76, r 2 ¼ 0.265), separated by a stretch of 87 kb and are located 5 0 from PRDM1. 8,25 Similarly, the PRDM1 SNPs emerging from the RA and SLE studies, rs548234 and rs6568431, respectively, are 21 kb apart, occur in LD (D 0 ¼ 0.92, r 2 ¼ 0.69), and both are located 3 0 from PRDM1.…”