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Association of RASGRP1 with type 1 diabetes is revealed by combined follow-up of two genome-wide studies
  1. Hui-Qi Qu (hui.qi.qu{at}mail.mcgill.ca)
  1. McGill University, Canada
    1. Struan FA Grant (grants{at}chop.edu)
    1. The Children’s Hospital of Philadelphia, United States
      1. Jonathan P Bradfield (bradfieldj{at}email.chop.edu)
      1. The Children’s Hospital of Philadelphia, United States
        1. Cecilia Kim (kimc{at}email.chop.edu)
        1. The Children’s Hospital of Philadelphia, United States
          1. Edward Frackelton (frackelton{at}email.chop.edu)
          1. The Children’s Hospital of Philadelphia, United States
            1. Hakon Hakonarson (hakonarson{at}chop.edu)
            1. The Children’s Hospital of Philadelphia, United States
              1. Constantin Polychronakos (constantin.polychronakos{at}mcgill.ca)
              1. McGill University, Canada

                Abstract

                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 analyzed data from two sources: 1) The previously published second stage of our study, with a total sample size of the two stages consisting of 1,046 Canadian case-parent trios and 538 multiplex families with 929 affected offspring from the Type 1 Diabetes Genetics Consortium (T1DGC); 2) The RR2 project of the T1DGC, which genotyped 4,417 individuals from 1,062 non-overlapping families, including 2,059 affected individuals (mostly sibling pairs) for the 1,536 markers with the highest statistical significance for type 1 diabetes in the WTCCC results.

                Results: One locus, mapping to an LD block at chr5q14, reached statistical significance by combining results from two markers (rs17574546 and rs7171171) in perfect linkage disequilibrium (LD) with each other (r2=1). We obtained a joint p value of 1.3 x10-6, which exceeds by an order of magnitude the conservative threshold of 3.26x10-5 obtained by correcting for the 1,536 SNPs tested in our study. Meta-analysis with the original WTCCC genome-wide data produced a p value of 5.83x10-9.

                Conclusions: A novel type 1 diabetes locus was discovered. It involves RASGRP1, a gene known to play a crucial role in thymocyte differentiation and TCR signaling by activating the Ras signaling pathway.

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