Scientists have carried out what they claim is the largest meta-analysis of type 1 diabetes genome-wide genotyped datasets, to identify new loci associated with type 1 diabetes. The highlighted regions, at 13q22, 2p23, and 6q27, were subsequently replicated in independent sample sets.
The Children’s Hospital of Philadelphia team says that the most significantly associated SNP (rs539514) at 13q22 resides in an intronic region of the LMO7 (LIM domain only 7) gene. The second SNP (rs478222), in terms of significance, resides in an intronic region of the EFR3B gene on 2p23, although the 800 kb region of linkage disequilibrium spans multiple genes. The SNP (rs924043) at 6q27, meanwhile, lies in an intergenic region where the region of association also harbors multiple genes.
Hakon Hakonarson, M.D., Jonathan P. Bradfield, M.D., and colleagues report their results in PLoS Genetics in a paper titled “A Genome-Wide Meta-Analysis of Six Type 1 Diabetes Cohorts Identifies Multiple Associated Loci.”
The researchers’ meta-analysis covered the combined data from six large publicly available datasets including some 10,000 type 1 diabetes patients and 17,000 controls. The cases and controls were initially split into two groups, dependent on whether they had been genotyped on the Illumina BeadChip platform or on Affymetrix arrays.
Fifty-three SNPs were then replicated in an independent cohort of patients and controls. The results found that three SNPS reached the threshold for genome-wide significance. The most significantly associated SNP (rs539514) is sited within the intronic region of LMO7, a gene that encodes a protein occurring in multiple isoforms, and which contains multiple domains, including a calponin homology domain, a PDZ domain, and a LIM domain.
Interestingly, the researchers note, while LMO7 is expressed in pancreatic islets and “thus is a possible biological candidate at this locus,” LMO7 mutations in humans are associated with the retinal, muscular development, and islet patterns in patients with Emery-Dreifuss muscular dystrophy, which bears little similarity to type 1 diabetes. Moreover, mice with homozygous deletions in LMO7 are also known to display retinal, muscular, and growth defects.
The second most significantly associated SNP (rs478222) resides in an intronic region of the EFR3B gene on 2p23, although the 800 kb region of linkage disequilibrium actually harbors multiple genes including 3NCOA1, C2orf79, CENPO, ADCY3, DNAJC27, POMC, and DNMT3A. A prior meta-analysis of a subset of the data used in the Children’s Hospital study identified an independent SNP, rs2165738, with a suggestive link to diabetes, but the association didn’t achieve genome-wide significance at the time, the authors note, and their study only found modest evidence of an association with rs2165738 in the discovery cohort. In contrast, the locus has also been associated with a risk allele for increased height or BMI, that was protective for type 1 diabetes risk.
The third most significantly associated SNP (rs924043) lies in an intergenic region on 6q27, with the 900 kb region of association harboring multiple genes including WDR27, C6orf120, PHF10, TCTE3, C6orf208, LOC154449, DLL1, FAM120B, PSMB1, TBP, and PCD2.
Three additional loci that didn’t reach genome-wide significance also showed evidence for association with type 1 diabetes, the researchers note. These regions contain the candidate genes LOC100128081, TNFRSF11B, and FOSL2. Of these, TNFRSF11B is a locus that prior GWAS have strongly associated with bone mineral density.