title: Evidence for two independent associations with type 1 diabetes at the 12q13 locus.
abstract: 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.
authors.affiliation: Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA.
authors.forename: K L
authors.initials: KL
authors.lastname: Keene
authors.forename: A R
authors.initials: AR
authors.lastname: Quinlan
authors.forename: X
authors.initials: X
authors.lastname: Hou
authors.forename: I M
authors.initials: IM
authors.lastname: Hall
authors.forename: J C
authors.initials: JC
authors.lastname: Mychaleckyj
authors.forename: S
authors.initials: S
authors.lastname: Onengut-Gumuscu
authors.forename: P
authors.initials: P
authors.lastname: Concannon
mesh_terms: D002881:Chromosomes, Human, Pair 12; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D056726:Genetic Association Studies; D056426:Genetic Loci; D020022:Genetic Predisposition to Disease; D006801:Humans; D020641:Polymorphism, Single Nucleotide; D035781:Siblings