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.
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.
One locus, mapping to an LD block at chr15q14, 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 ×10−6, which exceeds by an order of magnitude the conservative threshold of 3.26×10−5 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 5.83×10−9.
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.