204
views
0
recommends
+1 Recommend
1 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found

      Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease

      research-article
      1 , 2 , 2 , 1 , 2 , 1 , 3 , 4 , 5 , 6 , 7 , 8 , 1 , 6 , 1 , 2 , 9 , 10 , 11 , 1 , 1 , 12 , 1 , 2 , 1 , 11 , 13 , 14 , 15 , 16 , 11 , 17 , 6 , 18 , 1 , 19 , 17 , 14 , 20 , 8 , 21 , 22 , 1 , 23 , 11 , 24 , 1 , 21 , 25 , 8 , 26 , 18 , 27 , 28 , 8 , 20 , 29 , 30 , CEGEC (Spanish Consortium on the Genetics of Coeliac Disease), PreventCD Study Group, Wellcome Trust Case Control Consortium, 26 , 31 , 8 , 13 , 32 , 33 , 11 , 34 , 11 , 1 , 2
      Nature genetics

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          We densely genotyped, using 1000 Genomes Project pilot CEU and additional re-sequencing study variants, 183 reported immune-mediated disease non- HLA risk loci in 12,041 celiac disease cases and 12,228 controls. We identified 13 new celiac disease risk loci at genome wide significance, bringing the total number of known loci (including HLA) to 40. Multiple independent association signals are found at over a third of these loci, attributable to a combination of common, low frequency, and rare genetic variants. In comparison with previously available data such as HapMap3, our dense genotyping in a large sample size provided increased resolution of the pattern of linkage disequilibrium, and suggested localization of many signals to finer scale regions. In particular, 29 of 54 fine-mapped signals appeared localized to specific single genes - and in some instances to gene regulatory elements. We define a complex genetic architecture of risk regions, and refine risk signals, providing a next step towards elucidating causal disease mechanisms.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

          PLINK: a tool set for whole-genome association and population-based linkage analyses.

          Whole-genome association studies (WGAS) bring new computational, as well as analytic, challenges to researchers. Many existing genetic-analysis tools are not designed to handle such large data sets in a convenient manner and do not necessarily exploit the new opportunities that whole-genome data bring. To address these issues, we developed PLINK, an open-source C/C++ WGAS tool set. With PLINK, large data sets comprising hundreds of thousands of markers genotyped for thousands of individuals can be rapidly manipulated and analyzed in their entirety. As well as providing tools to make the basic analytic steps computationally efficient, PLINK also supports some novel approaches to whole-genome data that take advantage of whole-genome coverage. We introduce PLINK and describe the five main domains of function: data management, summary statistics, population stratification, association analysis, and identity-by-descent estimation. In particular, we focus on the estimation and use of identity-by-state and identity-by-descent information in the context of population-based whole-genome studies. This information can be used to detect and correct for population stratification and to identify extended chromosomal segments that are shared identical by descent between very distantly related individuals. Analysis of the patterns of segmental sharing has the potential to map disease loci that contain multiple rare variants in a population-based linkage analysis.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found
            Is Open Access

            A map of human genome variation from population-scale sequencing.

            The 1000 Genomes Project aims to provide a deep characterization of human genome sequence variation as a foundation for investigating the relationship between genotype and phenotype. Here we present results of the pilot phase of the project, designed to develop and compare different strategies for genome-wide sequencing with high-throughput platforms. We undertook three projects: low-coverage whole-genome sequencing of 179 individuals from four populations; high-coverage sequencing of two mother-father-child trios; and exon-targeted sequencing of 697 individuals from seven populations. We describe the location, allele frequency and local haplotype structure of approximately 15 million single nucleotide polymorphisms, 1 million short insertions and deletions, and 20,000 structural variants, most of which were previously undescribed. We show that, because we have catalogued the vast majority of common variation, over 95% of the currently accessible variants found in any individual are present in this data set. On average, each person is found to carry approximately 250 to 300 loss-of-function variants in annotated genes and 50 to 100 variants previously implicated in inherited disorders. We demonstrate how these results can be used to inform association and functional studies. From the two trios, we directly estimate the rate of de novo germline base substitution mutations to be approximately 10(-8) per base pair per generation. We explore the data with regard to signatures of natural selection, and identify a marked reduction of genetic variation in the neighbourhood of genes, due to selection at linked sites. These methods and public data will support the next phase of human genetic research.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls.

              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 P < 5 x 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals (including 58 loci with single-point P values between 10(-5) and 5 x 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.
                Bookmark

                Author and article information

                Journal
                9216904
                2419
                Nat Genet
                Nat. Genet.
                Nature genetics
                1061-4036
                1546-1718
                31 October 2011
                06 November 2011
                01 June 2012
                : 43
                : 12
                : 1193-1201
                Affiliations
                [1 ]Genetics Department, University Medical Center and University of Groningen, PO Box 30.001, 9700 RB Groningen, The Netherlands
                [2 ]Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London E1 2AT, United Kingdom
                [3 ]Department of Gastroenterology, VU Medical Center, 1007 MB Amsterdam, The Netherlands
                [4 ]Fondazione IRCCS Ospedale Maggiore Policlinico, Mangiagalli e Regina Elena, Milan, Italy.
                [5 ]Department of Medical Sciences, University of Milan, Milan, Italy.
                [6 ]Genome Centre, Barts and the London School of Medicine and Dentistry, John Vane Science Centre, Charterhouse Square, London, EC1M 6BQ, United Kingdom
                [7 ]Universitat Rovira I Virgili, Department of Paediatric Gastroenterology, Hospital Univesitari de Sant Joan de Reus, , 43201 Reus, Spain
                [8 ]Immunology Dept, Hospital Clínico S. Carlos, Instituto de Investigación Sanitaria San Carlos IdISSC, Madrid, Spain
                [9 ]Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
                [10 ]Department of Human Genetics, University of Pittsburgh Graduate School of Public Health, Pittsburgh, Pennsylvania, USA
                [11 ]Wellcome Trust Sanger Institute, Hinxton, Cambridge, CB10 1SA, United Kingdom
                [12 ]Department of Gastroenterology, University Medical Center and Groningen University, 9700 RB Groningen, The Netherlands
                [13 ]Immunogenetics Research Laboratory, Hospital de Cruces, Barakaldo 48903 Bizkaia, Spain
                [14 ]European Laboratory for Food Induced Disease, University of Naples Federico II, Naples, Italy.
                [15 ]Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [16 ]Nijmegen Institute for Infection, Inflammation and Immunity (N4i), Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
                [17 ]Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
                [18 ]Dayanand Medical College and Hospital, Ludhiana, Punjab, India
                [19 ]University of Maribor, Faculty of Medicine, Center for Human Molecular Genetics and Pharmacogenomics, Slomskov trg 15, 2000 Maribor, Slovenia
                [20 ]Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom
                [21 ]Center for Public Health Genomics, University of Virginia, Charlottesville, VA 22908-0717
                [22 ]UCL Genomics, Institute of Child Health, University College London, 30 Guilford Street, London WC1N 1EH, United Kingdom
                [23 ]Pediatrics Gastroenterology Department, Hospital La Paz, Madrid, Spain
                [24 ]La Fe University Hospital, Pediatric Gastroenterology, Bulevar Sur s/n 46026 Valencia, Spain
                [25 ]Department of Gastroenterology, Hepatology and Immunology, Children’s Memorial Health Institute, Warsaw, Poland
                [26 ]Department of Genetics, University of Delhi, South Campus, New Delhi, India.
                [27 ]The Medical University of Warsaw, Department of Pediatrics, Dzialdowska 1, 01-184 Warsaw, Poland
                [28 ]University of Naples, Fedrico II, Department of Pediatrics, Via S.Pansini 5, 80131 Naples, Italy
                [29 ]Department of Paediatric Gastroenterology, University Medical Centre Utrecht, Utrecht, The Netherlands
                [30 ]Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands
                [31 ]Department of Pathology, Children’s Memorial Health Institute, Warsaw, Poland
                [32 ]Department of Paediatrics, Leiden University Medical Centre, Leiden, The Netherlands
                [33 ]Department of Experimental Medicine, Faculty of Medicine University of Milano-Bicocca,Monza, Italy
                [34 ]UCL Genetics Institute, University College London, Gower Street, London WC1E 6BT
                Author notes
                [35]

                These authors contributed equally to this work

                [36]

                These authors jointly directed this project.

                AUTHOR CONTRIBUTIONS DAvH and C. Wijmenga led the study. Major contributions were (i) DAvH, KAH, GT and C. Wijmenga wrote the paper; (ii) KAH, GT, VM, NB, JR, MP, MM, RHD and KF performed DNA sample preparation and genotyping assays; (iii) DAvH, VP, KAH, GT performed statistical analysis. Other authors contributed mainly to sample collection and phenotyping. PD led the formation of the Immunochip Consortium, with SNP selection by JB and C. Wallace. All authors reviewed the final manuscript.

                Article
                UKMS37096
                10.1038/ng.998
                3242065
                22057235
                6588d85e-e373-4508-b743-fdb7215fde1a

                Users may view, print, copy, download and text and data- mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

                History
                Funding
                Funded by: Wellcome Trust :
                Award ID: 084743 || WT
                Funded by: Medical Research Council :
                Award ID: G1001158(95979) || MRC_
                Categories
                Article

                Genetics
                Genetics

                Comments

                Comment on this article