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1. Development of an integrated genome informatics, data management and workflow infrastructure: A toolbox for the study of complex disease genetics

Author

Burren Oliver S, Healy Barry C, Lam Alex C, Schuilenburg Helen, Dolman Geoffrey E, Everett Vincent H, Laneri Davide, Nutland Sarah, Rance Helen E, Payne Felicity, Smyth Deborah, Lowe Chris, Barratt Bryan J, Twells Rebecca CJ, Rainbow Daniel B, Wicker Linda S, Todd John A, Walker Neil M, and Smink Luc J

Subjects
type 1 diabetes, complex disease, genome informatics, data management, genetics, Medicine, Genetics, QH426-470
Abstract

Abstract The genetic dissection of complex disease remains a significant challenge. Sample-tracking and the recording, processing and storage of high-throughput laboratory data with public domain data, require integration of databases, genome informatics and genetic analyses in an easily updated and scaleable format. To find genes involved in multifactorial diseases such as type 1 diabetes (T1D), chromosome regions are defined based on functional candidate gene content, linkage information from humans and animal model mapping information. For each region, genomic information is extracted from Ensembl, converted and loaded into ACeDB for manual gene annotation. Homology information is examined using ACeDB tools and the gene structure verified. Manually curated genes are extracted from ACeDB and read into the feature database, which holds relevant local genomic feature data and an audit trail of laboratory investigations. Public domain information, manually curated genes, polymorphisms, primers, linkage and association analyses, with links to our genotyping database, are shown in Gbrowse. This system scales to include genetic, statistical, quality control (QC) and biological data such as expression analyses of RNA or protein, all linked from a genomics integrative display. Our system is applicable to any genetic study of complex disease, of either large or small scale.

Published
2004
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2. Evidence of association with type 1 diabetes in the SLC11A1 gene region

Author

Walker Neil M, Stevens Helen E, Nutland Sarah, Howson Joanna MM, Downes Kate, Yang Jennie HM, and Todd John A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background Linkage and congenic strain analyses using the nonobese diabetic (NOD) mouse as a model for human type 1 autoimmune diabetes (T1D) have identified several NOD mouse Idd (insulin dependent diabetes) loci, including Slc11a1 (formerly known as Nramp1). Genetic variants in the orthologous region encompassing SLC11A1 in human chromosome 2q35 have been reported to be associated with various immune-related diseases including T1D. Here, we have conducted association analysis of this candidate gene region, and then investigated potential correlations between the most T1D-associated variant and RNA expression of the SLC11A1 gene and its splice isoform. Methods Nine SNPs (rs2276631, rs2279015, rs1809231, rs1059823, rs17235409 (D543N), rs17235416 (3'UTR), rs3731865 (INT4), rs7573065 (-237 C→T) and rs4674297) were genotyped using TaqMan genotyping assays and the polymorphic promoter microsatellite (GT)n was genotyped using PCR and fragment length analysis. A maximum of 8,863 T1D British cases and 10,841 British controls, all of white European descent, were used to test association using logistic regression. A maximum of 5,696 T1D families were also tested for association using the transmission/disequilibrium test (TDT). We considered P ≤ 0.005 as evidence of association given that we tested nine variants in total. Upon identification of the most T1D-associated variant, we investigated the correlation between its genotype and SLC11A1 expression overall or with splice isoform ratio using 42 PAXgene whole blood samples from healthy donors by quantitative PCR (qPCR). Results Using the case-control collection, rs3731865 (INT4) was identified to be the variant most associated with T1D (P = 1.55 × 10-6). There was also some evidence of association at rs4674297 (P = 1.57 × 10-4). No evidence of disease association was obtained at any of the loci using the family collections (PTDT ≥ 0.13). We also did not observe a correlation between rs3731865 genotypes and SLC11A1 expression overall or with splice isoform expression. Conclusion We conclude that rs3731685 (INT4) in the SLC11A1 gene may be associated with T1D susceptibility in the European ancestry population studied. We did not observe a difference in SLC11A1 expression at the RNA level based on the genotypes of rs3731865 in whole blood samples. However, a potential correlation cannot be ruled out in purified cell subsets especially monocytes or macrophages.

Published
2011
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3. Sequencing and association analysis of the type 1 diabetes – linked region on chromosome 10p12-q11

Author

Barratt Bryan J, Twells Rebecca, Smith Anne, Walker Neil M, Nutland Sarah, Stevens Helen, Burren Oliver, Lam Alex, Godfrey Lisa, Masters Jennifer, Payne Felicity, Lowe Christopher E, Bailey Rebecca, Smyth Deborah, Smink Luc J, Nejentsev Sergey, Wright Charmain, French Lisa, Chen Yuan, Deloukas Panagiotis, Rogers Jane, Dunham Ian, and Todd John A

Subjects
Genetics, QH426-470
Abstract

Abstract Background In an effort to locate susceptibility genes for type 1 diabetes (T1D) several genome-wide linkage scans have been undertaken. A chromosomal region designated IDDM10 retained genome-wide significance in a combined analysis of the main linkage scans. Here, we studied sequence polymorphisms in 23 Mb on chromosome 10p12-q11, including the putative IDDM10 region, to identify genes associated with T1D. Results Initially, we resequenced the functional candidate genes, CREM and SDF1, located in this region, genotyped 13 tag single nucleotide polymorphisms (SNPs) and found no association with T1D. We then undertook analysis of the whole 23 Mb region. We constructed and sequenced a contig tile path from two bacterial artificial clone libraries. By comparison with a clone library from an unrelated person used in the Human Genome Project, we identified 12,058 SNPs. We genotyped 303 SNPs and 25 polymorphic microsatellite markers in 765 multiplex T1D families and followed up 22 associated polymorphisms in up to 2,857 families. We found nominal evidence of association in six loci (P = 0.05 – 0.0026), located near the PAPD1 gene. Therefore, we resequenced 38.8 kb in this region, found 147 SNPs and genotyped 84 of them in the T1D families. We also tested 13 polymorphisms in the PAPD1 gene and in five other loci in 1,612 T1D patients and 1,828 controls from the UK. Overall, only the D10S193 microsatellite marker located 28 kb downstream of PAPD1 showed nominal evidence of association in both T1D families and in the case-control sample (P = 0.037 and 0.03, respectively). Conclusion We conclude that polymorphisms in the CREM and SDF1 genes have no major effect on T1D. The weak T1D association that we detected in the association scan near the PAPD1 gene may be either false or due to a small genuine effect, and cannot explain linkage at the IDDM10 region.

Published
2007
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4. Discovery, linkage disequilibrium and association analyses of polymorphisms of the immune complement inhibitor, decay-accelerating factor gene (DAF/CD55) in type 1 diabetes

Author

Smink Luc J, Walker Neil M, Burren Oliver, Lam Alex C, Healy Barry C, Nutland Sarah, Bailey Rebecca, Smyth Deborah J, Cooper Jason D, Lowe Christopher E, Taniguchi Hidenori, Wicker Linda S, and Todd John A

Subjects
Genetics, QH426-470
Abstract

Abstract Background Type 1 diabetes (T1D) is a common autoimmune disease resulting from T-cell mediated destruction of pancreatic beta cells. Decay accelerating factor (DAF, CD55), a glycosylphosphatidylinositol-anchored membrane protein, is a candidate for autoimmune disease susceptibility based on its role in restricting complement activation and evidence that DAF expression modulates the phenotype of mice models for autoimmune disease. In this study, we adopt a linkage disequilibrium (LD) mapping approach to test for an association between the DAF gene and T1D. Results Initially, we used HapMap II genotype data to examine LD across the DAF region. Additional resequencing was required, identifying 16 novel polymorphisms. Combining both datasets, a LD mapping approach was adopted to test for association with T1D. Seven tag SNPs were selected and genotyped in case-control (3,523 cases and 3,817 controls) and family (725 families) collections. Conclusion We obtained no evidence of association between T1D and the DAF region in two independent collections. In addition, we assessed the impact of using only HapMap II genotypes for the selection of tag SNPs and, based on this study, found that HapMap II genotypes may require additional SNP discovery for comprehensive LD mapping of some genes in common disease.

Published
2006
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5. Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases

Author

Walker Neil M, Nutland Sarah, Lam Alex C, Dahlman Ingrid, Vella Adrian, Hulme John S, Cooper Jason D, Lowe Christopher E, Holland Kieran, Bailey Rebecca, Maier Lisa M, Payne Felicity, Howson Joanna MM, Smyth Deborah J, Twells Rebecca CJ, and Todd John A

Subjects
Internal medicine, RC31-1245, Genetics, QH426-470
Abstract

Abstract Background The identification of the HLA class II, insulin (INS), CTLA-4 and PTPN22 genes as determinants of type 1 diabetes (T1D) susceptibility indicates that fine tuning of the immune system is centrally involved in disease development. Some genes have been shown to affect several immune-mediated diseases. Therefore, we tested the hypothesis that alleles of susceptibility genes previously associated with other immune-mediated diseases might perturb immune homeostasis, and hence also associate with predisposition to T1D. Methods We resequenced and genotyped tag single nucleotide polymorphisms (SNPs) from two genes, CRP and FCER1B, and genotyped 27 disease-associated polymorphisms from thirteen gene regions, namely FCRL3, CFH, SLC9A3R1, PADI4, RUNX1, SPINK5, IL1RN, IL1RA, CARD15, IBD5-locus (including SLC22A4), LAG3, ADAM33 and NFKB1. These genes have been associated previously with susceptibility to a range of immune-mediated diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Graves' disease (GD), psoriasis, psoriatic arthritis (PA), atopy, asthma, Crohn disease and multiple sclerosis (MS). Our T1D collections are divided into three sample subsets, consisting of set 1 families (up to 754 families), set 2 families (up to 743 families), and a case-control collection (ranging from 1,500 to 4,400 cases and 1,500 to 4,600 controls). Each SNP was genotyped in one or more of these subsets. Our study typically had approximately 80% statistical power for a minor allele frequency (MAF) >5% and odds ratios (OR) of 1.5 with the type 1 error rate, α = 0.05. Results We found no evidence of association with T1D at most of the loci studied 0.02

Published
2006
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6. Construction and analysis of tag single nucleotide polymorphism maps for six human-mouse orthologous candidate genes in type 1 diabetes

Author

Savage David A, Ionescu-Tîrgovişte Constantin, Guja Cristian, Rønningen Kjersti S, Undlien Dag E, Nutland Sarah, Walker Neil, Chamberlain Giselle, Hunter Kara M, Moule Carolyn, Fraser Heather, Smink Luc J, Hulme John, Lowe Christopher, Pask Rebecca, Cooper Jason D, Payne Felicity, Vella Adrian, Smyth Deborah J, Maier Lisa M, Strachan David P, Peterson Laurence B, Todd John A, Wicker Linda S, and Twells Rebecca C

Subjects
Genetics, QH426-470
Abstract

Abstract Background One strategy to help identify susceptibility genes for complex, multifactorial diseases is to map disease loci in a representative animal model of the disorder. The nonobese diabetic (NOD) mouse is a model for human type 1 diabetes. Linkage and congenic strain analyses have identified several NOD mouse Idd (insulin dependent diabetes) loci, which have been mapped to small chromosome intervals, for which the orthologous regions in the human genome can be identified. Here, we have conducted re-sequencing and association analysis of six orthologous genes identified in NOD Idd loci: NRAMP1/SLC11A1 (orthologous to Nramp1/Slc11a1 in Idd5.2), FRAP1 (orthologous to Frap1 in Idd9.2), 4-1BB/CD137/TNFRSF9 (orthologous to 4-1bb/Cd137/Tnrfrsf9 in Idd9.3), CD101/IGSF2 (orthologous to Cd101/Igsf2 in Idd10), B2M (orthologous to B2m in Idd13) and VAV3 (orthologous to Vav3 in Idd18). Results Re-sequencing of a total of 110 kb of DNA from 32 or 96 type 1 diabetes cases yielded 220 single nucleotide polymorphisms (SNPs). Sixty-five SNPs, including 54 informative tag SNPs, and a microsatellite were selected and genotyped in up to 1,632 type 1 diabetes families and 1,709 cases and 1,829 controls. Conclusion None of the candidate regions showed evidence of association with type 1 diabetes (P values > 0.2), indicating that common variation in these key candidate genes does not play a major role in type 1 diabetes susceptibility in the European ancestry populations studied.

Published
2005
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7. Investigating the utility of combining Φ29 whole genome amplification and highly multiplexed single nucleotide polymorphism BeadArray™ genotyping

Author

Smink Luc J, Lam Alex C, Smith Anne, Twells Rebecca CJ, Sebastian Meera, Smyth Deborah J, Nutland Sarah, Barratt Bryan J, Rance Helen E, Pask Rebecca, Walker Neil M, and Todd John A

Subjects
Biotechnology, TP248.13-248.65
Abstract

Abstract Background Sustainable DNA resources and reliable high-throughput genotyping methods are required for large-scale, long-term genetic association studies. In the genetic dissection of common disease it is now recognised that thousands of samples and hundreds of thousands of markers, mostly single nucleotide polymorphisms (SNPs), will have to be analysed. In order to achieve these aims, both an ability to boost quantities of archived DNA and to genotype at low costs are highly desirable. We have investigated Φ29 polymerase Multiple Displacement Amplification (MDA)-generated DNA product (MDA product), in combination with highly multiplexed BeadArray™ genotyping technology. As part of a large-scale BeadArray genotyping experiment we made a direct comparison of genotyping data generated from MDA product with that from genomic DNA (gDNA) templates. Results Eighty-six MDA product and the corresponding 86 gDNA samples were genotyped at 345 SNPs and a concordance rate of 98.8% was achieved. The BeadArray sample exclusion rate, blind to sample type, was 10.5% for MDA product compared to 5.8% for gDNA. Conclusions We conclude that the BeadArray technology successfully produces high quality genotyping data from MDA product. The combination of these technologies improves the feasibility and efficiency of mapping common disease susceptibility genes despite limited stocks of gDNA samples.

Published
2004
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11. Negligible impact of rare autoimmune-locus coding-region variants on missing heritability

Author

Hunt, Karen A., Mistry, Vanisha, Bockett, Nicholas A., Ahmad, Tariq, Ban, Maria, Barker, Jonathan N., Barrett, Jeffrey C., Blackburn, Hannah, Brand, Oliver, Burren, Oliver, Capon, Francesca, Compston, Alastair, Gough, Stephen C. L., Jostins, Luke, Kong, Yong, Lee, James C., Lek, Monkol, MacArthur, Daniel G., Mansfield, John C., Mathew, Christopher G., Mein, Charles A., Mirza, Muddassar, Nutland, Sarah, Onengut-Gumuscu, Suna, Papouli, Efterpi, Parkes, Miles, Rich, Stephen S., Sawcer, Steven, Satsangi, Jack, Simmonds, Matthew J., Trembath, Richard C., Walker, Neil M., Wozniak, Eva, Todd, John A., Simpson, Michael A., Plagnol, Vincent, and van Heel, David A.

Published
2013
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12. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Author

Burton, Paul R., Clayton, David G., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Todd, John A., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Stevens, Helen E., Taylor, Niall C., Walters, Graham R., Walker, Neil M., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Ferrier, I. Nicol, Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Mohiuddin, M. Khalid, Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Marcano, Carolina A. Braga, Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Mohammed J. R., Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Widden, Claire, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingileif B., Howie, Bryan N., Su, Zhan, Teo, Yik Ying, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): The Wellcome Trust Case Control Consortium; Management Committee; Paul R. Burton [1]; David G. Clayton [2]; Lon R. Cardon [3]; Nick Craddock [4]; Panos Deloukas [5]; Audrey Duncanson [6]; [...]

Published
2007
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13. Localization of a type 1 diabetes locus in the IL2RA/CD25 region by use of tag single-nucleotide polymorphisms

Author

Vella, Adrian, Cooper, Jason D., Lowe, Christopher E., Walker, Neil, Nutland, Sarah, Widmer, Barry, Jones, Richard, Ring, Susan M., McArdle, Wendy, Pembrey, Marcus E., Strachan, David P., Dunger, David B., Twells, Rebecca C.J., Clayton, David G., and Todd, John A.

Subjects
Human genetics -- Research, Type 1 diabetes -- Research, Type 1 diabetes -- Genetic aspects, Biological sciences
Published
2005

14. Linkage and association mapping of the LRP5 locus on chromosome 11q13 in type 1 diabetes

Author

Twells, Rebecca C. J., Mein, Charles A., Payne, Felicity, Veijola, Riitta, Gilbey, Matthew, Bright, Matthew, Timms, Andrew, Nakagawa, Yusuke, Snook, Hywel, Nutland, Sarah, Rance, Helen E., Carr, Philippa, Dudbridge, Frank, Cordell, Heather J., Cooper, Jason, Tuomilehto-Wolf, Eva, Tuomilehto, Jaakko, Phillips, Michael, Metzker, Michael, Hess, J. Fred, and Todd, John A.

Published
2003
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15. Association of the T-cell regulatory gene CTLA4 with susceptibility to autoimmune disease

Author

Ueda, Hironori, Howson, Joanna M. M., Esposito, Laura, Heward, Joanne, Snook, Chamberlain, Giselle, Rainbow, Daniel B., Hunter, Kara M. D., Smith, Annabel N., Di Genova, Gianfranco, Herr, Mathias H., Dahlman, Ingrid, Payne, Felicity, Smyth, Deborah, Lowe, Christopher, Twells, Rebecca C. J., Howlett, Sarah, Healy, Barry, Nutland, Sarah, Rance, Helen E., Everett, Vin, Smink, Luc J., Lam, Alex C., Cordell, Heather J., Walker, Neil M., Bordin, Cristina, Hulme, John, Motzo, Costantino, Cucca, Francesco, Hess, J. Fred, Metzker, Michael L., Rogers, Jane, Gregory, Simon, Allahabadia, Amit, Nithiyananthan, Ratnasingam, Tuomilehto-Wolf, Eva, Tuomilehto, Jaakko, Bingley, Polly, Gillespie, Kathleen M., Undlien, Dag E., Rønningen, Kjersti S., Guja, Cristian, Ionescu-Tîrgovişte, Constantin, Savage, David A., Maxwell, A. Peter, Carson, Dennis J., Patterson, Chris C., Franklyn, Jayne A., Clayton, David G., Peterson, Laurence B., Wicker, Linda S., Todd, John A., and Gough, Stephen C. L.

Published
2003
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16. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J., Wallace, Chris, Cooper, Jason D., Cope, Nathan F., Wilson, Nicola K., Smyth, Deborah J., Howson, Joanna M.M., Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L., Stevens, Helen E., Nutland, Sarah, Duley, Simon, Coulson, Richard M.R., Walker, Neil M., Burren, Oliver S., Rice, Catherine M., Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, and Todd, John A.

Published
2012
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22. Replication of an Association Between the Lymphoid Tyrosine Phosphatase Locus (LYP/PTPN22) With Type 1 Diabetes, and Evidence for Its Role as a General Autoimmunity Locus

Author

Smyth, Deborah, Cooper, Jason D., Collins, Joanne E., Heward, Joanne M., Franklyn, Jayne A., Howson, Joanna M.M., Vella, Adrian, Nutland, Sarah, Rance, Helen E., Maier, Lisa, Barratt, Bryan J., Guja, Cristian, Ionescu-Tîrgovişte, Constantin, Savage, David A., Dunger, David B., Widmer, Barry, Strachan, David P., Ring, Susan M., Walker, Neil, Clayton, David G., Twells, Rebecca C.J., Gough, Stephen C.L., and Todd, John A.

Published
2004

23. Analysis of the Vitamin D Receptor Gene Sequence Variants in Type 1 Diabetes

Author

Nejentsev, Sergey, Cooper, Jason D., Godfrey, Lisa, Howson, Joanna M.M., Rance, Helen, Nutland, Sarah, Walker, Neil M., Guja, Cristian, Ionescu-Tirgovişte, Constantin, Savage, David A., Undlien, Dag E., Rønningen, Kjersti S., Tuomilehto-Wolf, Eva, Tuomilehto, Jaakko, Gillespie, Kathleen M., Ring, Susan M., Strachan, David P., Widmer, Barry, Dunger, David, and Todd, John A.

Published
2004

29. Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Author

Nejentsev, Sergey, Howson, Joanna M. M., Walker, Neil M., Szeszko, Jeffrey, Field, Sarah F., Stevens, Helen E., Reynolds, Pamela, Hardy, Matthew, King, Erna, Masters, Jennifer, Hulme, John, Maier, Lisa M., Smyth, Deborah, Bailey, Rebecca, Cooper, Jason D., Ribas, Gloria, Campbell, R. Duncan, Clayton, David G., Todd, John A., Burton, Paul R., Cardon, Lon R., Craddock, Nick, Deloukas, Panos, Duncanson, Audrey, Kwiatkowski, Dominic P., McCarthy, Mark I., Ouwehand, Willem H., Samani, Nilesh J., Donnelly, Peter, Barrett, Jeffrey C., Davison, Dan, Easton, Doug, Evans, David, Leung, Hin-Tak, Marchini, Jonathan L., Morris, Andrew P., Spencer, Chris C. A., Tobin, Martin D., Attwood, Antony P., Boorman, James P., Cant, Barbara, Everson, Ursula, Hussey, Judith M., Jolley, Jennifer D., Knight, Alexandra S., Koch, Kerstin, Meech, Elizabeth, Nutland, Sarah, Prowse, Christopher V., Taylor, Niall C., Walters, Graham R., Watkins, Nicholas A., Winzer, Thilo, Jones, Richard W., McArdle, Wendy L., Ring, Susan M., Strachan, David P., Pembrey, Marcus, Breen, Gerome, St Clair, David, Caesar, Sian, Gordon-Smith, Katherine, Jones, Lisa, Fraser, Christine, Green, Elaine K., Grozeva, Detelina, Hamshere, Marian L., Holmans, Peter A., Jones, Ian R., Kirov, George, Moskvina, Valentina, Nikolov, Ivan, O'Donovan, Michael C., Owen, Michael J., Collier, David A., Elkin, Amanda, Farmer, Anne, Williamson, Richard, McGuffin, Peter, Young, Allan H., Nicol Ferrier, I., Ball, Stephen G., Balmforth, Anthony J., Barrett, Jennifer H., Bishop, D. Timothy, Iles, Mark M., Maqbool, Azhar, Yuldasheva, Nadira, Hall, Alistair S., Braund, Peter S., Dixon, Richard J., Mangino, Massimo, Stevens, Suzanne, Thompson, John R., Bredin, Francesca, Tremelling, Mark, Parkes, Miles, Drummond, Hazel, Lees, Charles W., Nimmo, Elaine R., Satsangi, Jack, Fisher, Sheila A., Forbes, Alastair, Lewis, Cathryn M., Onnie, Clive M., Prescott, Natalie J., Sanderson, Jeremy, Mathew, Christopher G., Barbour, Jamie, Khalid Mohiuddin, M., Todhunter, Catherine E., Mansfield, John C., Ahmad, Tariq, Cummings, Fraser R., Jewell, Derek P., Webster, John, Brown, Morris J., Lathrop, G. Mark, Connell, John, Dominiczak, Anna, Braga, Carolina A., Burke, Beverley, Dobson, Richard, Gungadoo, Johannie, Lee, Kate L., Munroe, Patricia B., Newhouse, Stephen J., Onipinla, Abiodun, Wallace, Chris, Xue, Mingzhan, Caulfield, Mark, Farrall, Martin, Barton, Anne, Bruce, Ian N., Donovan, Hannah, Eyre, Steve, Gilbert, Paul D., Hider, Samantha L., Hinks, Anne M., John, Sally L., Potter, Catherine, Silman, Alan J., Symmons, Deborah P. M., Thomson, Wendy, Worthington, Jane, Dunger, David B., Widmer, Barry, Frayling, Timothy M., Freathy, Rachel M., Lango, Hana, Perry, John R. B., Shields, Beverley M., Weedon, Michael N., Hattersley, Andrew T., Hitman, Graham A., Walker, Mark, Elliott, Kate S., Groves, Christopher J., Lindgren, Cecilia M., Rayner, Nigel W., Timpson, Nicholas J., Zeggini, Eleftheria, Newport, Melanie, Sirugo, Giorgio, Lyons, Emily, Vannberg, Fredrik, Hill, Adrian V. S., Bradbury, Linda A., Farrar, Claire, Pointon, Jennifer J., Wordsworth, Paul, Brown, Matthew A., Franklyn, Jayne A., Heward, Joanne M., Simmonds, Matthew J., Gough, Stephen C. L., Seal, Sheila, Stratton, Michael R., Rahman, Nazneen, Ban, Maria, Goris, An, Sawcer, Stephen J., Compston, Alastair, Conway, David, Jallow, Muminatou, Rockett, Kirk A., Bryan, Claire, Bumpstead, Suzannah J., Chaney, Amy, Downes, Kate, Ghori, Jilur, Gwilliam, Rhian, Hunt, Sarah E., Inouye, Michael, Keniry, Andrew, King, Emma, McGinnis, Ralph, Potter, Simon, Ravindrarajah, Rathi, Whittaker, Pamela, Withers, David, Cardin, Niall J., Ferreira, Teresa, Pereira-Gale, Joanne, Hallgrimsdottir, Ingeleif B., Howie, Bryan N., Su, Zhan, Ying Teo, Yik, Vukcevic, Damjan, Bentley, David, and Compston, Alistair

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Sergey Nejentsev [1, 57]; Joanna M. M. Howson (corresponding author) [1, 57]; Neil M. Walker [1]; Jeffrey Szeszko [1]; Sarah F. Field [1]; Helen E. Stevens [1]; Pamela Reynolds [...]

Published
2007
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30. Association of intercellular adhesion molecule-1 gene with type 1 diabetes

Author

Nejentsev, Sergey, Guja, Cristian, McCormack, Rose, Copper, Jason, Howson, Joanna MM, Nutland, Sarah, Rance, Helen, Walker, Neil, Undlien, Dag, Ronningen, Kjersti S, Tuomilehto-Wolf, Eva, Tuomilehto, Jaakko, Ionescu-Tirgoviste, Constantin, Gale, Edwin AM, Bingley, Polly J, Gillespie, Kathleen M, Savage, David A, Carson, Dennis J, Patterson, Chris C, Maxwell, A Peter, and Todd, John A

Subjects
Cell adhesion molecules -- Physiological aspects, Type 1 diabetes -- Physiological aspects
Published
2003

31. Mo1816 The Impact of NOD2 Variants on Gut Microbiota in Crohn's Disease and Healthy Controls

Author

Kennedy, Nicholas A., primary, Walker, Alan W., additional, Berry, Susan H., additional, Lamb, Christopher A., additional, Lewis, Sophie, additional, Mansfield, John C., additional, Parkes, Miles, additional, Parkhill, Julian, additional, Probert, Chris, additional, Read, Debbie, additional, Satsangi, Jack, additional, Simpkins, Rachel L., additional, Tomlinson, David, additional, Tremelling, Mark, additional, Nutland, Sarah L., additional, Hold, Georgina L., additional, and Lees, Charlie W., additional

Published
2015
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32. Effective recruitment of participants to a phase I study using the internet and publicity releases through charities and patient organisations: analysis of the adaptive study of IL-2 dose on regulatory T cells in type 1 diabetes (DILT1D)

Author

Heywood, James, primary, Evangelou, Marina, additional, Goymer, Donna, additional, Kennet, Jane, additional, Anselmiova, Katerina, additional, Guy, Catherine, additional, O’Brien, Criona, additional, Nutland, Sarah, additional, Brown, Judy, additional, Walker, Neil M, additional, Todd, John A, additional, and Waldron-Lynch, Frank, additional

Published
2015
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33. A type 1 diabetes subgroup with a female bias is characterised by failure in tolerance to thyroid peroxidase at an early age and a strong CTLA-4 gene association

Author

Howson, Joanna M. M., Dunger, David B., Nutland, Sarah, Stevens, Helen, Wicker, Linda S., and Todd, John A.

Subjects
Male, Adolescent, Autoimmunity, Autoantigens, Iodide Peroxidase, Polymorphism, Single Nucleotide, Article, Sex Factors, Antigens, CD, Iron-Binding Proteins, Odds Ratio, Humans, CTLA-4 Antigen, Age of Onset, Child, Alleles, Protein Tyrosine Phosphatase, Non-Receptor Type 1, Infant, Newborn, Genetic Variation, Infant, Protein Tyrosine Phosphatase, Non-Receptor Type 22, Antigens, Differentiation, Diabetes Mellitus, Type 1, Child, Preschool, Female, Protein Tyrosine Phosphatases
Abstract

HLA haplotypes DRB1*03_DQB1*02 and DRB1*04_DQB1*0302, and allelic variation of the T cell regulatory gene cytotoxic T-lymphocyte-associated antigen-4 (CTLA4) and of the T cell activation gene protein tyrosine phosphatase, non-receptor type 22 (lymphoid) (PTPN22) have been associated with type 1 diabetes and autoimmune thyroid disease. Using thyroid peroxidase autoantibodies (TPOAbs) as an indicator of thyroid autoimmunity, we assessed whether the association of these loci is different in type 1 diabetes patients with TPOAbs than in those without.TPOAbs were measured in 4,364 type 1 diabetic patients from across Great Britain, 67% of whom were aged under 18 years. These patients and 6,866 geographically matched control subjects were genotyped at CTLA4, PTPN22, HLA-DRB1 and HLA-DQB1.TPOAbs were detected in 462 (10.6%) of the type 1 diabetic patients. These patients had a stronger association with CTLA4 (odds ratio [OR] = 1.49 for the G allele of the single nucleotide polymorphism rs3087243; 95% CI = 1.29-1.72) than did the TPOAbs-negative patients (p = 0.0004; OR = 1.16; 95% CI = 1.10-1.24) or type 1 diabetes patients overall (OR = 1.20; 95% CI = 1.13-1.27). The ratio of women:men was higher (1.94:1) in this subgroup than in type 1 diabetes patients without TPOAbs (0.94:1; p = 1.86 x 10(-15)). TPOAbs status did not correlate with age at diagnosis of type 1 diabetes or with PTPN22 (Arg620Trp; rs2476601).Our results identify a subgroup of type 1 diabetic patients that is sensitive to allelic variation of the negative regulatory molecule CTLA-4 and indicate that TPOAbs testing could be used to subclassify type 1 diabetes patients for inclusion in genetic, biological or clinical studies.

Published
2007

34. Investigation of Soluble and Transmembrane CTLA-4 Isoforms in Serum and Microvesicles

Author

Esposito, Laura, primary, Hunter, Kara M. D., additional, Clark, Jan, additional, Rainbow, Daniel B., additional, Stevens, Helen, additional, Denesha, Jennifer, additional, Duley, Simon, additional, Dawson, Sarah, additional, Coleman, Gillian, additional, Nutland, Sarah, additional, Bell, Gwynneth L., additional, Moran, Carla, additional, Pekalski, Marcin, additional, Todd, John A., additional, and Wicker, Linda S., additional

Published
2014
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35. The IL23R A/Gln381 Allele Promotes IL-23 Unresponsiveness in Human Memory T-Helper 17 Cells and Impairs Th17 Responses in Psoriasis Patients

Author

Di Meglio, Paola, primary, Villanova, Federica, additional, Napolitano, Luca, additional, Tosi, Isabella, additional, Barberio, Manuela Terranova, additional, Mak, Rose K., additional, Nutland, Sarah, additional, Smith, Catherine H., additional, Barker, Jonathan N.W.N., additional, Todd, John A., additional, and Nestle, Frank O., additional

Published
2014
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36. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J, Wallace, Chris, Cooper, Jason D, Cope, Nathan F, Wilson, Nicola K, Smyth, Deborah J, Howson, Joanna M M, Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L, Stevens, Helen E, Nutland, Sarah, Duley, Simon, Coulson, Richard M R, Walker, Neil M, Burren, Oliver S, Rice, Catherine M, Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, Todd, John A, Davison, Lucy J, Wallace, Chris, Cooper, Jason D, Cope, Nathan F, Wilson, Nicola K, Smyth, Deborah J, Howson, Joanna M M, Saleh, Nada, Al-Jeffery, Abdullah, Angus, Karen L, Stevens, Helen E, Nutland, Sarah, Duley, Simon, Coulson, Richard M R, Walker, Neil M, Burren, Oliver S, Rice, Catherine M, Cambien, Francois, Zeller, Tanja, Munzel, Thomas, Lackner, Karl, Blankenberg, Stefan, Fraser, Peter, Gottgens, Berthold, and Todd, John A

Abstract

The chromosome 16p13 region has been associated with several autoimmune diseases, including type 1 diabetes (T1D) and multiple sclerosis (MS). CLEC16A has been reported as the most likely candidate gene in the region, since it contains the most disease-associated single-nucleotide polymorphisms (SNPs), as well as an imunoreceptor tyrosine-based activation motif. However, here we report that intron 19 of CLEC16A, containing the most autoimmune disease-associated SNPs, appears to behave as a regulatory sequence, affecting the expression of a neighbouring gene, DEXI. The CLEC16A alleles that are protective from T1D and MS are associated with increased expression of DEXI, and no other genes in the region, in two independent monocyte gene expression data sets. Critically, using chromosome conformation capture (3C), we identified physical proximity between the DEXI promoter region and intron 19 of CLEC16A, separated by a loop of >150 kb. In reciprocal experiments, a 20 kb fragment of intron 19 of CLEC16A, containing SNPs associated with T1D and MS, as well as with DEXI expression, interacted with the promotor region of DEXI but not with candidate DNA fragments containing other potential causal genes in the region, including CLEC16A. Intron 19 of CLEC16A is highly enriched for transcription-factor-binding events and markers associated with enhancer activity. Taken together, these data indicate that although the causal variants in the 16p13 region lie within CLEC16A, DEXI is an unappreciated autoimmune disease candidate gene, and illustrate the power of the 3C approach in progressing from genome-wide association studies results to candidate causal genes., Per Lundmark and Ann-Christine Syvänen (Institution for Medical Sciences, Uppsala University, Uppsala, Sweden) contributed to this study.

Published
2012
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37. Plasma concentrations of soluble IL-2 receptor α (CD25) are increased in type 1 diabetes and associated with reduced C-peptide levels in young patients

Author

Downes, Kate, primary, Marcovecchio, M. Loredana, additional, Clarke, Pamela, additional, Cooper, Jason D., additional, Ferreira, Ricardo C., additional, Howson, Joanna M. M., additional, Jolley, Jennifer, additional, Nutland, Sarah, additional, Stevens, Helen E., additional, Walker, Neil M., additional, Wallace, Chris, additional, Dunger, David B., additional, and Todd, John A., additional

Published
2013
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38. The IL23R A/Gln381 Allele Promotes IL-23 Unresponsiveness in Human Memory T-Helper 17 Cells and Impairs Th17 Responses in Psoriasis Patients

Author

Di Meglio, Paola, primary, Villanova, Federica, additional, Napolitano, Luca, additional, Tosi, Isabella, additional, Terranova Barberio, Manuela, additional, Mak, Rose K., additional, Nutland, Sarah, additional, Smith, Catherine H., additional, Barker, Jonathan N.W.N., additional, Todd, John A., additional, and Nestle, Frank O., additional

Published
2013
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39. Postthymic Expansion in Human CD4 Naive T Cells Defined by Expression of Functional High-Affinity IL-2 Receptors

Author

Pekalski, Marcin L., primary, Ferreira, Ricardo C., additional, Coulson, Richard M. R., additional, Cutler, Antony J., additional, Guo, Hui, additional, Smyth, Deborah J., additional, Downes, Kate, additional, Dendrou, Calliope A., additional, Castro Dopico, Xaquin, additional, Esposito, Laura, additional, Coleman, Gillian, additional, Stevens, Helen E., additional, Nutland, Sarah, additional, Walker, Neil M., additional, Guy, Catherine, additional, Dunger, David B., additional, Wallace, Chris, additional, Tree, Timothy I. M., additional, Todd, John A., additional, and Wicker, Linda S., additional

Published
2013
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40. Type 1 Diabetes-Associated IL2RA Variation Lowers IL-2 Signaling and Contributes to Diminished CD4+CD25+ Regulatory T Cell Function

Author

Garg, Garima, primary, Tyler, Jennifer R., additional, Yang, Jennie H. M., additional, Cutler, Antony J., additional, Downes, Kate, additional, Pekalski, Marcin, additional, Bell, Gwynneth L., additional, Nutland, Sarah, additional, Peakman, Mark, additional, Todd, John A., additional, Wicker, Linda S., additional, and Tree, Timothy I. M., additional

Published
2012
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41. Long-range DNA looping and gene expression analyses identify DEXI as an autoimmune disease candidate gene

Author

Davison, Lucy J., primary, Wallace, Chris, additional, Cooper, Jason D., additional, Cope, Nathan F., additional, Wilson, Nicola K., additional, Smyth, Deborah J., additional, Howson, Joanna M.M., additional, Saleh, Nada, additional, Al-Jeffery, Abdullah, additional, Angus, Karen L., additional, Stevens, Helen E., additional, Nutland, Sarah, additional, Duley, Simon, additional, Coulson, Richard M.R., additional, Walker, Neil M., additional, Burren, Oliver S., additional, Rice, Catherine M., additional, Cambien, Francois, additional, Zeller, Tanja, additional, Munzel, Thomas, additional, Lackner, Karl, additional, Blankenberg, Stefan, additional, Fraser, Peter, additional, Gottgens, Berthold, additional, and Todd, John A., additional

Published
2011
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44. Cell-specific protein phenotypes for the autoimmune locus IL2RA using a genotype-selectable human bioresource

Author

Dendrou, Calliope A, primary, Plagnol, Vincent, additional, Fung, Erik, additional, Yang, Jennie H M, additional, Downes, Kate, additional, Cooper, Jason D, additional, Nutland, Sarah, additional, Coleman, Gillian, additional, Himsworth, Matthew, additional, Hardy, Matthew, additional, Burren, Oliver, additional, Healy, Barry, additional, Walker, Neil M, additional, Koch, Kerstin, additional, Ouwehand, Willem H, additional, Bradley, John R, additional, Wareham, Nicholas J, additional, Todd, John A, additional, and Wicker, Linda S, additional

Published
2009
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45. F.5. Cell-specific CD25 Expression is Determined by Type 1 Diabetes Associated IL2RA Haplotypes

Author

Dendrou, Calliope, primary, Plagnol, Vincent, additional, Fung, Erik, additional, Downes, Kate, additional, Cooper, Jason, additional, Nutland, Sarah, additional, Coleman, Gillian, additional, Himsworth, Matthew, additional, Hardy, Matthew, additional, Burren, Oliver, additional, Healy, Barry, additional, Walker, Neil, additional, Koch, Kerstin, additional, Ouwehand, Willem, additional, Bradley, John, additional, Wareham, Nicholas, additional, Todd, John, additional, and Wicker, Linda, additional

Published
2009
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46. Sequencing and association analysis of the type 1 diabetes – linked region on chromosome 10p12-q11

Author

Nejentsev, Sergey, primary, Smink, Luc J, additional, Smyth, Deborah, additional, Bailey, Rebecca, additional, Lowe, Christopher E, additional, Payne, Felicity, additional, Masters, Jennifer, additional, Godfrey, Lisa, additional, Lam, Alex, additional, Burren, Oliver, additional, Stevens, Helen, additional, Nutland, Sarah, additional, Walker, Neil M, additional, Smith, Anne, additional, Twells, Rebecca, additional, Barratt, Bryan J, additional, Wright, Charmain, additional, French, Lisa, additional, Chen, Yuan, additional, Deloukas, Panagiotis, additional, Rogers, Jane, additional, Dunham, Ian, additional, and Todd, John A, additional

Published
2007
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48. Discovery, linkage disequilibrium and association analyses of polymorphisms of the immune complement inhibitor, decay-accelerating factor gene (DAF/CD55) in type 1 diabetes

Author

Taniguchi, Hidenori, primary, Lowe, Christopher E, additional, Cooper, Jason D, additional, Smyth, Deborah J, additional, Bailey, Rebecca, additional, Nutland, Sarah, additional, Healy, Barry C, additional, Lam, Alex C, additional, Burren, Oliver, additional, Walker, Neil M, additional, Smink, Luc J, additional, Wicker, Linda S, additional, and Todd, John A, additional

Published
2006
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49. Analysis of polymorphisms in 16 genes in type 1 diabetes that have been associated with other immune-mediated diseases

Author

Smyth, Deborah J, primary, Howson, Joanna MM, additional, Payne, Felicity, additional, Maier, Lisa M, additional, Bailey, Rebecca, additional, Holland, Kieran, additional, Lowe, Christopher E, additional, Cooper, Jason D, additional, Hulme, John S, additional, Vella, Adrian, additional, Dahlman, Ingrid, additional, Lam, Alex C, additional, Nutland, Sarah, additional, Walker, Neil M, additional, Twells, Rebecca CJ, additional, and Todd, John A, additional

Published
2006
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50. Population structure, differential bias and genomic control in a large-scale, case-control association study

Author

Clayton, David G, primary, Walker, Neil M, additional, Smyth, Deborah J, additional, Pask, Rebecca, additional, Cooper, Jason D, additional, Maier, Lisa M, additional, Smink, Luc J, additional, Lam, Alex C, additional, Ovington, Nigel R, additional, Stevens, Helen E, additional, Nutland, Sarah, additional, Howson, Joanna M M, additional, Faham, Malek, additional, Moorhead, Martin, additional, Jones, Hywel B, additional, Falkowski, Matthew, additional, Hardenbol, Paul, additional, Willis, Thomas D, additional, and Todd, John A, additional

Published
2005
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