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

Genes & Immunity volume 13, pages 66–70 (2012)Cite this article

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.

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Acknowledgements

This research utilizes resources provided by the Type 1 Diabetes Genetics Consortium, a collaborative clinical study sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institute of Allergy and Infectious Diseases (NIAID), National Human Genome Research Institute (NHGRI), National Institute of Child Health and Human Development (NICHD) and Juvenile Diabetes Research Foundation International (JDRF), and supported by U01 DK062418. This work was supported by grant DK46635 and a Juvenile Diabetes Research Foundation Postdoctoral Fellowship (KLK).

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Authors and Affiliations

  1. Department of Biochemistry and Molecular Genetics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA

    K L Keene, A R Quinlan, I M Hall & P Concannon

  2. Center for Public Health Genomics, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA

    K L Keene, A R Quinlan, X Hou, J C Mychaleckyj, S Onengut-Gumuscu & P Concannon

  3. Department of Public Health Sciences, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA

    A R Quinlan, X Hou & J C Mychaleckyj

  4. Division of Endocrinology and Metabolism, UVA School of Medicine, University of Virginia, Charlottesville, VA, USA

    S Onengut-Gumuscu

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  1. K L Keene
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Correspondence to P Concannon.

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Keene, K., Quinlan, A., Hou, X. et al. Evidence for two independent associations with type 1 diabetes at the 12q13 locus. Genes Immun 13, 66–70 (2012). https://doi.org/10.1038/gene.2011.56

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