1. Center for Applied Genomics, and,
2. Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
3. Department of Pediatrics and Division of Human Genetics, and,
4. Division of Endocrinology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA
5. Departments of Pediatrics and Human Genetics, McGill University, Montreal H3H 1P3, Québec, Canada
6. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg R3E 0Z2, Manitoba, Canada
7. Division of Endocrinology, Children's Hospital of Eastern Ontario, University of Ottawa, Ottawa K1H 8L1, Ontario, Canada
8. Markham-Stouffville Hospital, Markham L3P 7P3, Ontario, Canada
9. The Children's Hospital of Philadelphia Nucleic Acid and Protein Core, Philadelphia, Pennsylvania 19104, USA
10. Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA
11. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA
12. These authors contributed equally to this work.

Correspondence to: Hakon Hakonarson^1,3,12Constantin Polychronakos⁵ Correspondence and requests for materials should be addressed to H.H. (Email: hakonarson@chop.edu) or C.P. (Email: constantin.polychronakos@mcgill.ca).

Abstract

Type 1 diabetes (T1D) in children results from autoimmune destruction of pancreatic beta cells, leading to insufficient production of insulin¹. A number of genetic determinants of T1D have already been established through candidate gene studies, primarily within the major histocompatibility complex^{2, 3, 4} but also within other loci^{5, 6, 7, 8, 9, 10, 11, 12}. To identify new genetic factors that increase the risk of T1D, we performed a genome-wide association study in a large paediatric cohort of European descent. In addition to confirming previously identified loci^{2, 3, 4, 5, 6, 7, 8, 9}, we found that T1D was significantly associated with variation within a 233-kb linkage disequilibrium block on chromosome 16p13. This region contains KIAA0350, the gene product of which is predicted to be a sugar-binding, C-type lectin. Three common non-coding variants of the gene (rs2903692, rs725613 and rs17673553) in strong linkage disequilibrium reached genome-wide significance for association with T1D. A subsequent transmission disequilibrium test replication study in an independent cohort confirmed the association. These results indicate that KIAA0350 might be involved in the pathogenesis of T1D and demonstrate the utility of the genome-wide association approach in the identification of previously unsuspected genetic determinants of complex traits.

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