We have carried out the largest meta-analysis of genome wide genotyped datasets for T1D to date. The replication of three loci using the stratification-free TDT with minimal Mendelian error clearly indicates that they are not false positives due to artifacts such as uncorrected systematic error from stratification or genotyping bias.
The most significantly associated SNP (rs539514, P
) resides in an intronic region of the LMO7
(LIM domain only 7) gene on 13q22. We investigated the associated region using LocusZoom 
and determined that it is the only gene residing within the block of linkage disequilibrium harboring the signal (Figure S3
). Regional plots showing P
-values, linkage disequilibrium, and recombination rate for all SNPs in are outlined in the Figures S2
encodes a protein that contains multiple domains, including a calponin homology domain, a PDZ domain and a LIM domain. There are multiple LMO7 isoforms already known but their full nature and the actual extent of different isoforms remains unclear 
. Mice with homozygous deletions of LMO7
display retinal, muscular, and growth retardation 
. Although the function of LMO7 doesn't clearly relate to the etiology of T1D, LMO7
is expressed in pancreatic islets and thus is a possible biological candidate at this locus 
; however it should be noted that the retinal, muscular development and islet patterns are a key element in Emery-Dreifuss Muscular Dystrophy, caused by mutations in LMO7 
, but bears very little similarity to T1D.
The second most significantly associated SNP (rs478222, P
) resides in an intronic region of the EFR3B
(protein EFR3 homolog B) gene on 2p23; however the region of linkage disequilibrium is approximately 800 kb and harbors additional multiple genes, including 3NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC
, and DNMT3A
. (Figure S2
). A previous meta-analysis of a subset of the data used in this current study found suggestive association with T1D in the same LD block with the independent SNP, rs2165738(r2
0.115), but did not achieve genome wide significance at that time (P
; however, we only found modest evidence of association with rs2165738 (P
) in our discovery cohort. There has also been association to inflammatory bowel disease 
and BMI 
reported at this locus, where in both cases the risk allele for increased height or BMI was protective for T1D risk.
The third most significantly associated SNP (rs924043, P
) lies in an intergenic region on 6q27, where the region of association is approximately 900 kb and harbors multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP
). In addition, despite not reaching the bar for genome wide significance, we did observe evidence for association at three additional loci () containing the candidate genes LOC100128081
Of these, it is notable that TNFRSF11B
is a strongly associated locus with bone mineral density, also as a consequence of GWAS 
. In addition, the locus harboring LOC100128081
has also been reported in the context of a GWAS of SLE 
. Further work will be required to fully validate the role of these particular loci in the pathogenesis of T1D.
The Barrett et al
. meta-analysis was able to use British controls with British cases and American controls with American cases 
. We did not have the same control data to be able to make the same comparisons. In the case of the Affymetrix analysis, some American cases were analyzed with purely British controls and, in the case of the Illumina analysis, some British cases with purely American controls. As such, we were forced to make our corrections using eigenvectors as covariates in our analysis; this will have the effect of modestly weakening the level of significance for associations that vary in allele frequency between the cases and controls, as now the case and controls will both vary with the eigenvectors to some degree. This in effect will make our analysis overly conservative with estimating the true effect of a SNP, and in fact every SNP that had a P
-value less than 0.05 in the replication set did indeed have a greater effect than that which was estimated from the discovery set.
In summary, we provide convincing evidence for the existence of three additional loci associated with the T1D, adding to the repertoire of over 50 loci already demonstrated to be associated with the disease.