There is increasing evidence that genome-wide association (GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study (using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined approximately 2,000 individuals for each of 7 major diseases and a shared set of approximately 3,000 controls. Case-control comparisons identified 24 independent association signals at

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...

The discovery of a series of genetic and serological markers associated with disease susceptibility and phenotype in inflammatory bowel disease has led to the prospect of an integrated classification system involving clinical, serological and genetic parameters. The Working Party has reviewed current clinical classification systems in Crohn's disease, ulcerative colitis and indeterminate colitis, and provided recommendations for clinical classification in practice. Progress with respect to integrating serological and genetic markers has been examined in detail, and the implications are discussed. While an integrated system is not proposed for clinical use at present, the introduction of a widely acceptable clinical subclassification is strongly advocated, which would allow detailed correlations among serotype, genotype and clinical phenotype to be examined and confirmed in independent cohorts of patients and, thereby, provide a vital foundation for future work.

Nucleotide-binding oligomerization domain-containing-2 (NOD2) acts as a bacterial sensor in dendritic cells (DCs), but it is not clear how bacterial recognition links with antigen presentation after NOD2 stimulation. NOD2 variants are associated with Crohn's disease, where breakdown in self-recognition of commensal bacteria leads to gastrointestinal inflammation. Here we show NOD2 triggering by muramyldipeptide induces autophagy in DCs. This effect requires receptor-interacting serine-threonine kinase-2 (RIPK-2), autophagy-related protein-5 (ATG5), ATG7 and ATG16L1 but not NLR family, pyrin domain containing-3 (NALP3).We show that NOD2-mediated autophagy is required for both bacterial handling and generation of major histocompatibility complex (MHC) class II antigen-specific CD4(+) T cell responses in DCs. DCs from individuals with Crohn's disease expressing Crohn's disease-associated NOD2 or ATG16L1 risk variants are defective in autophagy induction, bacterial trafficking and antigen presentation. Our findings link two Crohn's disease-associated susceptibility genes in a single functional pathway and reveal defects in this pathway in Crohn's disease DCs that could lead to bacterial persistence via impaired lysosomal destruction and immune mediated clearance.

Elevated blood pressure is a common, heritable cause of cardiovascular disease worldwide. To date, identification of common genetic variants influencing blood pressure has proven challenging. We tested 2.5m genotyped and imputed SNPs for association with systolic and diastolic blood pressure in 34,433 subjects of European ancestry from the Global BPgen consortium and followed up findings with direct genotyping (N≤71,225 European ancestry, N=12,889 Indian Asian ancestry) and in silico comparison (CHARGE consortium, N=29,136). We identified association between systolic or diastolic blood pressure and common variants in 8 regions near the CYP17A1 (P=7×10−24), CYP1A2 (P=1×10−23), FGF5 (P=1×10−21), SH2B3 (P=3×10−18), MTHFR (P=2×10−13), c10orf107 (P=1×10−9), ZNF652 (P=5×10−9) and PLCD3 (P=1×10−8) genes. All variants associated with continuous blood pressure were associated with dichotomous hypertension. These associations between common variants and blood pressure and hypertension offer mechanistic insights into the regulation of blood pressure and may point to novel targets for interventions to prevent cardiovascular disease.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

We tested 310,605 single-nucleotide polymorphisms for association in 778 celiac disease cases and 1422 controls. Outside the HLA, the most significant finding (rs13119723, P=2.0 × 10 −7 , empirical genome-wide significance P=0.045) was in the KIAA1109/Tenr/IL2/IL21 linkage disequilibrium block. Association was independently confirmed in two further collections (strongest at rs6822844, 24kB 5' of IL21, meta-analysis P=1.3 × 10 −14 , OR 0.63), suggesting genetic variation in this region predisposes to celiac disease.Celiac disease is a common (1% prevalence) small intestinal inflammatory condition induced by dietary wheat, rye, and barley. However despite high heritability (estimated at 87% from twin studies1), no non-HLA genetic factors have been identified and convincingly replicated. The majority of celiacs possess HLA-DQ2 (the remainder mostly HLA-DQ82), and how HLA-DQ2 presents cereal peptides to intestinal T cells is understood3. However HLA-DQ2 is common in healthy individuals, demonstrating it is necessary but not sufficient for disease development.

Celiac disease is a genetic condition that results in a debilitating immune reaction in the gut to antigens in grain. The antigenic peptides recognized by the T cells that cause this disease are incompletely defined. Our understanding of the epitopes of pathogenic CD4(+ )T cells is based primarily on responses shown by intestinal T-cells in vitro to hydrolysates or polypeptides of gluten, the causative antigen. A protease-resistant 33-amino acid peptide from wheat alpha-gliadin is the immunodominant antigen, but little is known about the spectrum of T cell epitopes in rye and barley or the hierarchy of immunodominance and consistency of recognition of T-cell epitopes in vivo. We induced polyclonal gluten-specific T cells in the peripheral blood of celiac patients by feeding them cereal and performed a comprehensive, unbiased analysis of responses to all celiac toxic prolamins, a class of plant storage protein. The peptides that stimulated T cells were the same among patients who ate the same cereal, but were different after wheat, barley and rye ingestion. Unexpectedly, a sequence from omega-gliadin (wheat) and C-hordein (barley) but not alpha-gliadin was immunodominant regardless of the grain consumed. Furthermore, T cells specific for just three peptides accounted for the majority of gluten-specific T cells, and their recognition of gluten peptides was highly redundant. Our findings show that pathogenic T cells in celiac disease show limited diversity, and therefore suggest that peptide-based therapeutics for this disease and potentially other strongly HLA-restricted immune diseases should be possible.