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...

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.

A genome-wide association scan in Crohn disease by the Wellcome Trust Case Control Consortium1 detected strong association at 6 novel loci. We tested 37 SNPs from these and other loci for association in an independent case control sample. Replication was obtained for the IRGM gene on chromosome 5q33.1 which induces autophagy (replication P = 6.6 × 10 −4 , combined P = 2.1 × 10 −10 ), and for 9 other loci including NKX2-3 and gene deserts on chromosomes 1q and 5p13. Crohn disease (CD) is a common form of chronic inflammatory bowel disease. Established CD susceptibility genes NOD2 (CARD15), IL23R and ATG16L1 2-5 showed strong evidence of association in the Wellcome Trust Case Control Consortium (WTCCC) genome-wide scan of 1748 CD cases and 2938 controls genotyped using the Affymetrix 500K chip. Six other loci also showed highly significant association. Although satisfying stringent statistical thresholds for significance (P < 5 × 10 −7 ), replication in independent panels represents a key validation step.We followed up 37 SNPs from 31 distinct loci associated at P < 10 −5 on initial analysis of the WTCCC dataset. Support for some of these markers diminished in the final WTCCC analysis after extensive data filtering1. Three other associations with genome-wide significance in the WTCCC scan produced strong evidence of replication (P≤0.01), two of which are novel. The strongest was SNP rs9292777 (P rep =2.9×10 −7 ; P comb =3.2×10 −18 ) which maps to a 1.2 Mb gene desert on chromosome 5p13.1 recently associated with CD.9 The most significant novel association was SNP rs10883365 (P rep =0.0037, P comb =3.7 × 10 −10 ), which maps within the NKX2-3 gene (NK2 transcription factor related, locus 3) on chromosome 10q24.2. Nkx2.3-deficient mice develop splenic and gut-associated lymphoid tissue abnormalities with disordered segregation of T-and B-cells.10 The second novel locus at rs9858542 (P rep =0.010, P comb =4.9×10 −8 ) on chromosome 3p21 is a 1 Mb region of high LD that contains over 20 genes, including MST1 (macrophage stimulating 1), encoding a protein which induces phagocytosis by resident peritoneal macrophages.The modest evidence of replication for SNP rs2542151 (P = 0.048) at the PTPN2 locus (protein tyrosine phosphatase, non-receptor type 2) on chromosome 18p11 (P comb = 3.2 × 10 −8 ) is of interest since PTPN2 encodes a T cell protein tyrosine phosphatase, a key negative regulator of inflammation and is also associated with Type 1 Diabetes.11 Allele frequencies for rs10761659 on chromosome 10q21, strongly associated in the WTCCC scan, were similar in replication CD cases and population controls (SOM table 2), but association in this intergenic region was recently detected in a North American whole-genome CD scan. 12Allele frequencies for most of the markers from the 25 other loci studied that did not achieve genome-wide significance in the WTCCC scan but had an initial P<10 −5 converged with control frequencies in the CD replication panel (Supplementary Table 2). Five of these loci, however, provided ev...