Taken together, our full second-stage approach and combined meta-analysis have revealed additional loci associated with type 1 diabetes. Clearly the risks are relatively modest compared with previously described associations, and it was only with this sample size at our disposal that we could we detect and establish these signals as true positives through an independent validation effort.
is the only gene in its corresponding region of linkage disequilibrium. Mice lacking Sts2
(the mouse homologue for UBASH3A
) have been shown to be normal in all respects, including T-cell function (20
). Mice lacking both Sts1
do have increased splenocyte numbers and are hyper-responsive to T-cell receptor stimulation. It has been suggested that STS1 and STS2 are critical regulators of the signaling pathways that control T-cell activation (20
is also the only gene at its corresponding region of linkage disequilibrium. The gene product is a member of the small Maf family, which consists of basic region leucine zipper proteins that function either as transcriptional activators or repressors depending on the proteins with which they heterodimerize. Muto et al. (21
) found that Bach2−/−
mice had relatively high levels of serum IgM but low levels of IgA and IgG subclasses. The Bach2−/−
mice have also been reported to present with deficient T-cell–independent and T-cell–dependent IgG responses, leading the authors to conclude that BACH2 was a regulator of the antibody response.
It should also be noted that rs1983853 yielded a nominally significant association with type 1 diabetes in all of the cohorts but did not survive correction for multiple testing in the final validation attempt in the Toronto dataset. This SNP resides in endothelial differentiation gene 7 (EDG7
; formerly LPA3
), which has been implicated in mechanisms of embryo implantation (22
). The SNPs on GLIS3
were not validated. They may have been false positives in the earlier stages; alternatively, lack of replication in DCCT/EDIC may be due to different and/or weaker genetic risk determinants in this cohort with late age of onset of type 1 diabetes. This question must be addressed in future studies. The GLI-similar 3 (GLIS3
) gene plays important roles in the development of pancreatic β-cells. Mutations in this gene cause a rare syndrome with neonatal diabetes and congenital hypothyroidism (23
). The RAS guanyl releasing protein 1 (RASGRP1
) gene has important roles in immune regulation, and it has been suggested that it contributes to the autoimmunity of systemic lupus erythematosus (24
In addition to our findings, what we failed to find deserves comment. In addition to the findings described above, our study confirmed another interesting locus, rs17696736 (C12orf30
) at 12q24, reported in the WTCCC study (4
). Our GWA family cohort suggested type 1 diabetes association with P
= 0.011; however, limited by the sample size, our GWA case-control cohort did not show statistical significance (P
> 0.05). To validate the type 1 diabetes association, we genotyped rs17696736 using the Sequenom iPLEX assay (Sequenom, Cambridge, MA) in the 1,120 Canadian families and the 549 Type 1 Diabetes Genetics Consortium families. The call rate of rs17696736 genotyping was 99.8%, and no Mendelian error was found. With the family-based association test (25
), we confirmed the type 1 diabetes association with P
= 8.00 × 10−7
, minor G allele frequency 0.452, and OR 1.276. However, given the very thorough coverage of European genetic variation by the Hap550 and the power of our aggregate sample size, it is very unlikely that we missed more than a very small number of common variants with an effect size approaching that of the INS
(minor allele frequency 0.2 and OR 0.5; each of our three discovery cohorts has >99.9% power to detect it at α = 0.05 level) or PTPN22
(minor allele frequency 0.1 and OR 1.8; each of our three discovery cohorts has >99.0% power to detect it at α = 0.05 level) loci.
Undoubtedly, larger sample sizes and meta-analysis of all available GWA data will discover an increasing number of loci with decreasing effect sizes, which are unlikely to explain the remaining familial clustering of type 1 diabetes. Such explanation should be sought, it appears, in rare variants, the detection of which is now coming within reach with the use of high-throughput methods for sequencing and for detecting structural variation.