Abstract
Using variants from the 1000 Genomes Project pilot European CEU dataset and data from additional resequencing studies, we densely genotyped 183 non-HLA risk loci previously associated with immune-mediated diseases in 12,041 individuals with celiac disease (cases) and 12,228 controls. We identified 13 new celiac disease risk loci reaching genome-wide significance, bringing the number of known loci (including the HLA locus) to 40. We found multiple independent association signals at over one-third of these loci, a finding that is attributable to a combination of common, low-frequency and rare genetic variants. Compared to previously available data such as those from HapMap3, our dense genotyping in a large sample collection provided a higher resolution of the pattern of linkage disequilibrium and suggested localization of many signals to finer scale regions. In particular, 29 of the 54 fine-mapped signals seemed to be localized to single genes and, in some instances, to gene regulatory elements. Altogether, we define the complex genetic architecture of the risk regions of and refine the risk signals for celiac disease, providing the next step toward uncovering the causal mechanisms of the disease.
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Acknowledgements
We thank Coeliac UK for assistance with direct recruitment of individuals with celiac disease and the clinicians from the UK (L.C. Dinesen, G.K.T. Holmes, P.D. Howdle, J.R.F. Walters, D.S. Sanders, J. Swift, R. Crimmins, P. Kumar, D.P. Jewell, S.P.L. Travis and K. Moriarty) who recruited individuals with celiac disease to provide blood samples as described in our previous studies. We thank the Dutch clinicians for recruiting individuals with celiac disease to provide blood samples as described in our previous studies (C.J. Mulder, G.J. Tack, W.H.M. Verbeek, R.H.J. Houwen and J.J. Schweizer). We thank the genotyping facility of the University Medical Center Groningen (UMCG) (P. van der Vlies) for help in generating some of the Immunochip data and S. Jankipersadsing and A. Maatman at the UMCG for preparation of the samples. We thank R. Scott for preparing samples for genotyping and the staff at the University of Pittsburgh Genomics and Proteomics Core Laboratories for performing the genotyping. We thank C. Wallace for assistance with Immunochip SNP selection and J. Stone for coordinating the Immunochip design and production at Illumina. We thank the members of each disease consortium who initiated and sustained the cross-disease Immunochip project. We thank all individuals with celiac disease and all controls for participating in this study.
Funding was provided by the Wellcome Trust (084743 to D.A.v.H.), by grants from the Celiac Disease Consortium and an Innovative Cluster approved by the Netherlands Genomics Initiative. Partial funding was provided by the Dutch Government (BSIK03009 to C. Wijmenga) and the Netherlands Organisation for Scientific Research (NWO, grant 918.66.620 to C. Wijmenga). Funding was also provided by the US National Institutes of Health grant 1R01CA141743 (to R.H.D.) and Fondo de Investigación Sanitaria grants FIS08/1676 and FIS07/0353 (to E.U.). This research utilized resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases, the National Institute of Allergy and Infectious Diseases, the National Human Genome Research Institute, the National Institute of Child Health and Human Development and the Juvenile Diabetes Research Foundation International and is supported by the US National Institutes of Health grant U01-DK062418. We acknowledge use of DNA from The UK Blood Services collection of Common Controls (UKBS-CC collection), which is funded by the Wellcome Trust grant 076113/C/04/Z and by US National Institute for Health Research program grant to the National Health Service Blood and Transplant (RP-PG-0310-1002). The collection was established as part of the WTCCC33. We acknowledge the use of DNA from the British 1958 Birth Cohort collection, which is funded by the UK Medical Research Council grant G0000934 and the Wellcome Trust grant 068545/Z/02. S.S. is supported by a Senior Research Fellowship from the Council for Scientific and Industrial Research (CSIR), New Dehli, India.
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D.A.v.H. and C. Wijmenga led the study. D.A.v.H., K.A.H., G.T. and C. Wijmenga wrote the paper. K.A.H., G.T., V.Mistry, N.A.B., J.R., M.P., M.Mitrovic, R.H.D. and K.F. performed DNA sample preparation and genotyping assays. D.A.v.H., V.P., K.A.H. and G.T. performed the statistical analysis. All other authors contributed primarily to the sample collection and phenotyping. P.D. led the formation of the Immunochip Consortium, and SNP selection was performed by J.C.B. and C. Wallace. All authors reviewed the final manuscript.
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A list of members is provided in the Supplementary Note.
A list of members is provided in the Supplementary Note.
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Supplementary Text and Figures
Supplementary Note, Supplementary Tables 3 and 5 and Supplementary Figures 1 and 2. (PDF 5648 kb)
Supplementary Table 1
Comparison of risk signals reported in our 2010 celiac disease GWAS versus the current Immunochip dataset (XLSX 59 kb)
Supplementary Table 2
Functional annotation of identified risk variants and strongly correlated (r2 > 0.9) variants (XLSX 75 kb)
Supplementary Table 4
Genotype count and allele frequency data by sample collection and affection status (XLSX 33 kb)
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Trynka, G., Hunt, K., Bockett, N. et al. Dense genotyping identifies and localizes multiple common and rare variant association signals in celiac disease. Nat Genet 43, 1193–1201 (2011). https://doi.org/10.1038/ng.998
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DOI: https://doi.org/10.1038/ng.998
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