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

• Published in: Genes and immunity Vol. 13; no. 1; pp. 66 - 70
• Main Authors: Keene, K L, Quinlan, A R, Hou, X, Hall, I M, Mychaleckyj, J C, Onengut-Gumuscu, S, Concannon, P
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 01.01.2012
• Subjects: Chromosome 12; Chromosomes; Chromosomes, Human, Pair 12; Data processing; Diabetes; Diabetes mellitus; Diabetes mellitus (insulin dependent); Diabetes Mellitus, Type 1 - genetics; Epidermal growth factor; ErbB-3 protein; Exons; Genes; Genetic aspects; Genetic Association Studies; Genetic Loci; Genetic Predisposition to Disease; Genome-wide association studies; Genomes; Genomics; Genotyping; Humans; Kinases; Medicine; Polymorphism, Single Nucleotide; Proteins; Public health; Risk factors; Siblings; Single nucleotide polymorphisms; Single-nucleotide polymorphism; Type 1 diabetes; United States; United States > US
• ISSN: 1466-4879; 1476-5470
• DOI: 10.1038/gene.2011.56

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 ∼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. In all, 15 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 2740 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.