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Mary Fortune, Chris Wallace and colleagues report a new method that allows statistical colocalization of genetic risk variants for related autoimmune diseases in the context of common controls. They apply their method to type 1 diabetes, rheumatoid arthritis, celiac disease and multiple sclerosis and highlight the complexity in genetic variation underlying these distinct autoimmune diseases. Determining whether potential causal variants for related diseases are shared can identify overlapping etiologies of multifactorial disorders. Colocalization methods disentangle shared and distinct causal variants. However, existing approaches require independent data sets. Here we extend two colocalization methods to allow for the shared-control design commonly used in comparison of genome-wide association study results across diseases. Our analysis of four autoimmune diseases—type 1 diabetes (T1D), rheumatoid arthritis, celiac disease and multiple sclerosis—identified 90 regions that were associated with at least one disease, 33 (37%) of which were associated with 2 or more disorders. Nevertheless, for 14 of these 33 shared regions, there was evidence that the causal variants differed. We identified new disease associations in 11 regions previously associated with one or more of the other 3 disorders. Four of eight T1D-specific regions contained known type 2 diabetes (T2D) candidate genes ( COBL , GLIS3 , RNLS and BCAR1 ), suggesting a shared cellular etiology.

Type 1 diabetes and celiac disease, both of which are associated with HLA class II genes, cosegregate in populations, suggesting a common genetic origin. In this article, the authors tested whether any non-HLA loci are shared. They report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders. Type 1 diabetes and celiac disease cosegregate in populations, suggesting a common genetic origin. These authors report susceptibility alleles shared by both diseases, indicating that common biologic mechanisms underlie these immune-mediated disorders. Type 1 diabetes is caused by autoimmune destruction of the insulin-producing beta cells in the pancreatic islets. The disease affects approximately 0.4% of persons of European origin and is strongly clustered in families. The major susceptibility genes — the HLA class II loci, HLA-DQB1 and HLA-DRB1 on chromosome 6p21 — act in combination with many other non-HLA loci across the genome, 1 , 2 with unknown environmental factors playing a major role. 3 – 6 Celiac disease, which results from an immune, inflammatory reaction in the small intestine to proteins in ingested barley, wheat, and rye gluten, occurs in approximately 0.1% of persons of . . .

Jason Cooper and colleagues identify four new risk loci for type 1 diabetes through a meta-analysis of data from three genome-wide association studies, with replication in additional case-control and family-based samples, providing further insights into the genetic risk factors underlying this disease. We carried out a meta-analysis of data from three genome-wide association (GWA) studies of type 1 diabetes (T1D), testing 305,090 SNPs in 3,561 T1D cases and 4,646 controls of European ancestry. We obtained further support for 4q27 ( IL2-IL21 , P = 1.9 × 10 −8 ) and, after genotyping an additional 6,225 cases, 6,946 controls and 2,828 families, convincing evidence for four previously unknown and distinct risk loci in chromosome regions 6q15 ( BACH2 , P = 4.7 × 10 −12 ), 10p15 ( PRKCQ , P = 3.7 × 10 −9 ), 15q24 ( CTSH , P = 3.2 × 10 −15 ) and 22q13 ( C1QTNF6 , P = 2.0 × 10 −8 ).

IFIH1 (interferon induced with helicase C domain 1), also known as MDA5 (melanoma differentiation-associated protein 5), is one of a family of intracellular proteins known to recognise viral RNA and mediate the innate immune response. IFIH1 is causal in type 1 diabetes based on the protective associations of four rare variants, where the derived alleles are predicted to reduce gene expression or function. Originally, however, T1D protection was mapped to the common IFIH1 nsSNP, rs1990760 or Thr946Ala. This common amino acid substitution does not cause a loss of function and evidence suggests the protective allele, Ala(946), may mark a haplotype with reduced expression of IFIH1 in line with the protection conferred by the four rare loss of function alleles. We have performed allele specific expression analysis that supports this hypothesis: the T1D protective haplotype correlates with reduced IFIH1 transcription in interferon-β stimulated peripheral blood mononuclear cells (overall p = 0.012). In addition, we have used multiflow cytometry analysis and quantitative PCR assays to prove reduced expression of IFIH1 in individuals heterozygous for three of the T1D-associated rare alleles: a premature stop codon, rs35744605 (Glu627X) and predicted splice variants, rs35337543 (IVS8+1) and rs35732034 (IVS14+1). We also show that the nsSNP, Ile923V, does not alter pre-mRNA levels of IFIH1. These results confirm and extend the new autoimmune disease pathway of reduced IFIH1 expression and protein function protecting from T1D.

FUT2 encodes the α(1,2) fucosyltransferase that determines blood group secretor status. Homozygotes (A/A) for the common nonsense mutation rs601338A>G (W143X) are nonsecretors and are unable to express histo-blood group antigens in secretions and on mucosal surfaces. This mutation has been reported to provide resistance to Norovirus and susceptibility to Crohn's disease, and hence we aimed to determine if it also affects risk of type 1 diabetes. rs601338A>G was genotyped in 8,344 patients with type 1 diabetes, 10,008 control subjects, and 3,360 type 1 diabetic families. Logistic regression models were used to analyze the case-control collection, and conditional logistic regression was used to analyze the family collection. RESULTS The nonsecretor A/A genotype of rs601338A>G was found to confer susceptibility to type 1 diabetes in both the case-control and family collections (odds ratio for AA 1.29 [95% CI 1.20-1.37] and relative risk for AA 1.22 [95% CI = 1.12-1.32]; combined P = 4.3 × 10(-18)), based on a recessive effects model. Our findings linking FUT2 and type 1 diabetes highlight the intriguing relationship between host resistance to infections and susceptibility to autoimmune disease.

In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard ) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A → G (A946T) was 0.86 (95% confidence interval = 0.82–0.90) at P = 1.42 × 10 −10 .

Genome-wide association studies are now identifying disease-associated chromosome regions. However, even after convincing replication, the localization of the causal variant(s) requires comprehensive resequencing, extensive genotyping and statistical analyses in large sample sets leading to targeted functional studies. Here, we have localized the type 1 diabetes (T1D) association in the interleukin 2 receptor alpha ( IL2RA ) gene region to two independent groups of SNPs, spanning overlapping regions of 14 and 40 kb, encompassing IL2RA intron 1 and the 5′ regions of IL2RA and RBM17 (odds ratio = 2.04, 95% confidence interval = 1.70–2.45; P = 1.92 × 10 −28 ; control frequency = 0.635). Furthermore, we have associated IL2RA T1D susceptibility genotypes with lower circulating levels of the biomarker, soluble IL-2RA ( P = 6.28 × 10 −28 ), suggesting that an inherited lower immune responsiveness predisposes to T1D.

The main problems in drawing causal inferences from epidemiological case-control studies are confounding by unmeasured extraneous factors, selection bias and differential misclassification of exposure 1 . In genetics the first of these, in the form of population structure, has dominated recent debate 2 , 3 , 4 . Population structure explained part of the significant +11.2% inflation of test statistics we observed in an analysis of 6,322 nonsynonymous SNPs in 816 cases of type 1 diabetes and 877 population-based controls from Great Britain. The remainder of the inflation resulted from differential bias in genotype scoring between case and control DNA samples, which originated from two laboratories, causing false-positive associations. To avoid excluding SNPs and losing valuable information, we extended the genomic control method 2 , 3 , 4 , 5 by applying a variable downweighting to each SNP.

Identification of candidate causal variants in regions associated with risk of common diseases is complicated by linkage disequilibrium (LD) and multiple association signals. Nonetheless, accurate maps of these variants are needed, both to fully exploit detailed cell specific chromatin annotation data to highlight disease causal mechanisms and cells, and for design of the functional studies that will ultimately be required to confirm causal mechanisms. We adapted a Bayesian evolutionary stochastic search algorithm to the fine mapping problem, and demonstrated its improved performance over conventional stepwise and regularised regression through simulation studies. We then applied it to fine map the established multiple sclerosis (MS) and type 1 diabetes (T1D) associations in the IL-2RA (CD25) gene region. For T1D, both stepwise and stochastic search approaches identified four T1D association signals, with the major effect tagged by the single nucleotide polymorphism, rs12722496. In contrast, for MS, the stochastic search found two distinct competing models: a single candidate causal variant, tagged by rs2104286 and reported previously using stepwise analysis; and a more complex model with two association signals, one of which was tagged by the major T1D associated rs12722496 and the other by rs56382813. There is low to moderate LD between rs2104286 and both rs12722496 and rs56382813 (r2 ≃ 0:3) and our two SNP model could not be recovered through a forward stepwise search after conditioning on rs2104286. Both signals in the two variant model for MS affect CD25 expression on distinct subpopulations of CD4+ T cells, which are key cells in the autoimmune process. The results support a shared causal variant for T1D and MS. Our study illustrates the benefit of using a purposely designed model search strategy for fine mapping and the advantage of combining disease and protein expression data.

Association of the Vitamin D Metabolism Gene CYP27B1 With Type 1 Diabetes Rebecca Bailey 1 , Jason D. Cooper 1 , Lauren Zeitels 1 , Deborah J. Smyth 1 , Jennie H.M. Yang 1 , Neil M. Walker 1 , Elina Hyppönen 2 , David B. Dunger 3 , Elizabeth Ramos-Lopez 4 , Klaus Badenhoop 4 , Sergey Nejentsev 1 and John A. Todd 1 1 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, U.K 2 Centre for Paediatric Epidemiology and Biostatistics, Institute of Child Health, London, U.K 3 Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge, U.K 4 Department of Internal Medicine I, Division of Endocrinology, Diabetes, and Metabolism, University Hospital, Frankfurt, Germany Address correspondence and reprint requests to Prof. John A. Todd, Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, WT/MRC building, Addenbrooke's Hospital, Cambridge, CB2 0XY, U.K. E-mail: john.todd{at}cimr.cam.ac.uk Abstract OBJECTIVE— Epidemiological studies have linked vitamin D deficiency with the susceptibility to type 1 diabetes. Higher levels of the active metabolite 1α,25-dihydroxyvitamin D (1α,25(OH) 2 D) could protect from immune destruction of the pancreatic β-cells. 1α,25(OH) 2 D is derived from its precursor 25-hydroxyvitamin D by the enzyme 1α-hydroxylase encoded by the CYP27B1 gene and is inactivated by 24-hydroxylase encoded by the CYP24A1 gene. Our aim was to study the association between the CYP27B1 and CYP24A1 gene polymorphisms and type 1 diabetes. RESEARCH DESIGN AND METHODS— We studied 7,854 patients with type 1 diabetes, 8,758 control subjects from the U.K., and 2,774 affected families. We studied four CYP27B1 variants, including common polymorphisms −1260C>A (rs10877012) and +2838T>C (rs4646536) and 16 tag polymorphisms in the CYP24A1 gene. RESULTS— We found evidence of association with type 1 diabetes for CYP27B1 −1260 and +2838 polymorphisms, which are in perfect linkage disequilibrium. The common C allele of CYP27B1 −1260 was associated with an increased disease risk in the case-control analysis (odds ratio for the C/C genotype 1.22, P = 9.6 × 10 −4 ) and in the fully independent collection of families (relative risk for the C/C genotype 1.33, P = 3.9 × 10 −3 ). The combined P value for an association with type 1 diabetes was 3.8 × 10 −6 . For the CYP24A1 gene, we found no evidence of association with type 1 diabetes (multilocus test, P = 0.23). CONCLUSIONS— The present data provide evidence that common inherited variation in the vitamin D metabolism affects susceptibility to type 1 diabetes. 1α,25(OH)2D, 1α,25-dihydroxyvitamin D 25(OH)D, 25-hydroxyvitamin D EFSD, European Foundation for the Study of Diabetes IL, interleukin MAF, minor allele frequency NCBI, National Center for Biotechnology Information SNP, single nucleotide polymorphism VDR, vitamin D receptor Footnotes Published ahead of print at http://diabetes.diabetesjournals.org on 2 July 2007. DOI: 10.2337/db07-0652. Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/db07-0652 . The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Accepted June 27, 2007. Received May 15, 2007. DIABETES