Evidence for two independent associations with type 1 diabetes at the 12q13 locus

Genome-wide association studies have identified associations between type 1 diabetes and single nucleotide polymorphisms (SNPs) at chromosome 12q13, surrounding the gene ERBB3. Our objective was to fine map this region to further localize causative variants. Re-sequencing identified more than 100 putative SNPs in an 80 kb region at 12q13. By genotyping 42 SNPs, spanning approximately 214 kb, in 382 affected sibling pair type 1 diabetes families, we were able to genotype or tag 67 common SNPs (MAF ≥ 0.05) identified from HapMap CEU data and CEU data from the 1000 Genomes Project, plus additional rare coding variants identified from our re-sequencing efforts. Fifteen SNPs provided nominal evidence for association (P≤ 0.05) with type 1 diabetes. The most significant associations were observed with rs2271189 (P = 4.22×10(−5)), located in exon 27 of the ERBB3 gene, and an intergenic SNP rs11171747 (P= 1.70×10(−4)). Follow-up genotyping of these SNPs in 2 740 multiplex type 1 diabetes families validated these findings. After analyzing variants spanning more than 200 kb, we have replicated associations from previous GWAS and provide evidence for novel associations with type 1 diabetes. The associations across this region could be entirely accounted for by two common SNPs, rs2271189 and rs11171747.