BACKGROUND: The two genome-wide association studies published by us and by the Wellcome Trust Case-Control Consortium (WTCCC) revealed a number of novel loci, but neither had the statistical power to elucidate all of the genetic components of type 1 diabetes risk, a task for which larger effective sample sizes are needed. METHODS: We analysed data from two sources: (1) The previously published second stage of our study, with a total sample size of the two stages consisting of 1046 Canadian case-parent trios and 538 multiplex families with 929 affected offspring from the Type 1 Diabetes Genetics Consortium (T1DGC); (2) the Rapid Response 2 (RR2) project of the T1DGC, which genotyped 4417 individuals from 1062 non-overlapping families, including 2059 affected individuals (mostly sibling pairs) for the 1536 markers with the highest statistical significance for type 1 diabetes in the WTCCC results. RESULTS: One locus, mapping to a linkage disequilibrium (LD) block at chr15q14, reached statistical significance by combining results from two markers (rs17574546 and rs7171171) in perfect LD with each other (r2 = 1). We obtained a joint p value of 1.3 x 10(-6), which exceeds by an order of magnitude the conservative threshold of 3.26 x 10(-5) obtained by correcting for the 1536 single nucleotide polymorphisms (SNPs) tested in our study. Meta-analysis with the original WTCCC genome-wide data produced a p value of 5.83 x 10(-9). CONCLUSIONS: A novel type 1 diabetes locus was discovered. It involves RASGRP1, a gene known to play a crucial role in thymocyte differentiation and T cell receptor (TCR) signalling by activating the Ras signalling pathway.
BACKGROUND: The two genome-wide association studies published by us and by the Wellcome Trust Case-Control Consortium (WTCCC) revealed a number of novel loci, but neither had the statistical power to elucidate all of the genetic components of type 1 diabetes risk, a task for which larger effective sample sizes are needed. METHODS: We analysed data from two sources: (1) The previously published second stage of our study, with a total sample size of the two stages consisting of 1046 Canadian case-parent trios and 538 multiplex families with 929 affected offspring from the Type 1 Diabetes Genetics Consortium (T1DGC); (2) the Rapid Response 2 (RR2) project of the T1DGC, which genotyped 4417 individuals from 1062 non-overlapping families, including 2059 affected individuals (mostly sibling pairs) for the 1536 markers with the highest statistical significance for type 1 diabetes in the WTCCC results. RESULTS: One locus, mapping to a linkage disequilibrium (LD) block at chr15q14, reached statistical significance by combining results from two markers (rs17574546 and rs7171171) in perfect LD with each other (r2 = 1). We obtained a joint p value of 1.3 x 10(-6), which exceeds by an order of magnitude the conservative threshold of 3.26 x 10(-5) obtained by correcting for the 1536 single nucleotide polymorphisms (SNPs) tested in our study. Meta-analysis with the original WTCCC genome-wide data produced a p value of 5.83 x 10(-9). CONCLUSIONS: A novel type 1 diabetes locus was discovered. It involves RASGRP1, a gene known to play a crucial role in thymocyte differentiation and T cell receptor (TCR) signalling by activating the Ras signalling pathway.
Authors: Hakon Hakonarson; Struan F A Grant; Jonathan P Bradfield; Luc Marchand; Cecilia E Kim; Joseph T Glessner; Rosemarie Grabs; Tracy Casalunovo; Shayne P Taback; Edward C Frackelton; Margaret L Lawson; Luke J Robinson; Robert Skraban; Yang Lu; Rosetta M Chiavacci; Charles A Stanley; Susan E Kirsch; Eric F Rappaport; Jordan S Orange; Dimitri S Monos; Marcella Devoto; Hui-Qi Qu; Constantin Polychronakos Journal: Nature Date: 2007-07-15 Impact factor: 49.962
Authors: Anne M Norment; Lisa Y Bogatzki; Mark Klinger; Ethan W Ojala; Michael J Bevan; Robert J Kay Journal: J Immunol Date: 2003-02-01 Impact factor: 5.422
Authors: John A Todd; Neil M Walker; Jason D Cooper; Deborah J Smyth; Kate Downes; Vincent Plagnol; Rebecca Bailey; Sergey Nejentsev; Sarah F Field; Felicity Payne; Christopher E Lowe; Jeffrey S Szeszko; Jason P Hafler; Lauren Zeitels; Jennie H M Yang; Adrian Vella; Sarah Nutland; Helen E Stevens; Helen Schuilenburg; Gillian Coleman; Meeta Maisuria; William Meadows; Luc J Smink; Barry Healy; Oliver S Burren; Alex A C Lam; Nigel R Ovington; James Allen; Ellen Adlem; Hin-Tak Leung; Chris Wallace; Joanna M M Howson; Cristian Guja; Constantin Ionescu-Tîrgovişte; Matthew J Simmonds; Joanne M Heward; Stephen C L Gough; David B Dunger; Linda S Wicker; David G Clayton Journal: Nat Genet Date: 2007-06-06 Impact factor: 38.330
Authors: Struan F A Grant; Hui-Qi Qu; Jonathan P Bradfield; Luc Marchand; Cecilia E Kim; Joseph T Glessner; Rosemarie Grabs; Shayne P Taback; Edward C Frackelton; Andrew W Eckert; Kiran Annaiah; Margaret L Lawson; F George Otieno; Erin Santa; Julie L Shaner; Ryan M Smith; Robert Skraban; Marcin Imielinski; Rosetta M Chiavacci; Robert W Grundmeier; Charles A Stanley; Susan E Kirsch; Daryl Waggott; Andrew D Paterson; Dimitri S Monos; Constantin Polychronakos; Hakon Hakonarson Journal: Diabetes Date: 2008-10-07 Impact factor: 9.461
Authors: Sharon A Chung; Gang Xie; Delnaz Roshandel; Richard Sherva; Jeffrey C Edberg; Megan Kravitz; Paul F Dellaripa; Gary S Hoffman; Alfred D Mahr; Philip Seo; Ulrich Specks; Robert F Spiera; E William St Clair; John H Stone; Robert M Plenge; Katherine A Siminovitch; Peter A Merkel; Paul A Monach Journal: Arthritis Rheum Date: 2012-10