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A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene

Nature volume 448, pages 591–594 (2007)Cite this article

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 complex2,3,4 but also within other loci5,6,7,8,9,10,11,12. 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 loci2,3,4,5,6,7,8,9, 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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Figure 1: Pairwise linkage disequilibrium diagram of the KIAA0350 locus on 16p13.13.

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Acknowledgements

We acknowledge the use of DNA samples from the T1DGC, funded by the NIH. We thank all participating subjects and families. A. Belisle, A. W. Eckert, A. Estevez, K. Fain, R. Frechette, P. Kline, C. C. Onyiah, G. Otieno, E. Santa, J. L. Shaner, R. M. Smith, A. Thomas and L. Williams helped with genotyping or data collection and management. We thank D. Laforte and the PRUDENT team for subject recruitment and all T1DGC coordinating teams. We also thank S. Kristinsson, L. A. Hermannsson and A. Krisbjörnsson for their software design and contribution. This research was financially supported by the Children’s Hospital of Philadelphia, Genome Canada through the Ontario Genomics Institute and the Juvenile Diabetes Research Foundation.

Author Contributions H.H. and C.P. designed the study and supervised the data analysis and interpretation. S.F.A.G., J.P.B. and M.D. conducted the statistical analyses. C.E.K, T.C., E.C.F. and R.S. directed the genotyping of stage 1. H-Q.Q. and C.P. coordinated the genotyping and data analysis for stage 2. Y.L. and H-Q.Q. performed the resequencing and allelic-imbalance experiments. J.S.O. and E.F.R. carried out the work on NKT expression. J.P.B., J.T.G. and L.J.R. provided bioinformatics support. The remaining authors coordinated the studies used in stage 1 and 2. H.H., S.F.A.G., J.P.B., H-Q.Q. and C.P. drafted the manuscript.

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Author notes

  1. Hakon Hakonarson, Struan F. A. Grant and Jonathan P. Bradfield: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for Applied Genomics, and,,

    Hakon Hakonarson, Struan F. A. Grant, Jonathan P. Bradfield, Cecilia E. Kim, Joseph T. Glessner, Tracy Casalunovo, Edward C. Frackelton, Luke J. Robinson, Robert Skraban & Rosetta M. Chiavacci

  2. Department of Pathology and Laboratory Medicine, Abramson Research Center, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA,

    Dimitri S. Monos

  3. Department of Pediatrics and Division of Human Genetics, and,

    Hakon Hakonarson, Struan F. A. Grant & Marcella Devoto

  4. Division of Endocrinology, The Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA,

    Charles A. Stanley

  5. Departments of Pediatrics and Human Genetics, McGill University, Montreal H3H 1P3, Québec, Canada,

    Luc Marchand, Rosemarie Grabs, Yang Lu, Hui-Qi Qu & Constantin Polychronakos

  6. Department of Pediatrics and Child Health, University of Manitoba, Winnipeg R3E 0Z2, Manitoba, Canada,

    Shayne P. Taback

  7. Division of Endocrinology, Children’s Hospital of Eastern Ontario, University of Ottawa, Ottawa K1H 8L1, Ontario, Canada,

    Margaret L. Lawson

  8. Markham-Stouffville Hospital, Markham L3P 7P3, Ontario, Canada,

    Susan E. Kirsch

  9. The Children’s Hospital of Philadelphia Nucleic Acid and Protein Core, Philadelphia, Pennsylvania 19104, USA,

    Eric F. Rappaport

  10. Department of Pediatrics, University of Pennsylvania, School of Medicine, Philadelphia, Pennsylvania 19104, USA,

    Jordan S. Orange & Dimitri S. Monos

  11. Center for Clinical Epidemiology and Biostatistics, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA,

    Marcella Devoto

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Correspondence to Hakon Hakonarson or Constantin Polychronakos.

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Supplementary Information

This file contains Supplementary Methods, Supplementary Tables S1-S3, Supplementary Figures S1 and S2 with Legends and additional references. This file was corrected on 20 July 2007. (PDF 1101 kb)

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Hakonarson, H., Grant, S., Bradfield, J. et al. A genome-wide association study identifies KIAA0350 as a type 1 diabetes gene. Nature 448, 591–594 (2007). https://doi.org/10.1038/nature06010

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