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A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region

Nature Genetics 38, 617–619 (2006) | Download Citation

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Abstract

In this study we report convincing statistical support for a sixth type 1 diabetes (T1D) locus in the innate immunity viral RNA receptor gene region IFIH1 (also known as mda-5 or Helicard) on chromosome 2q24.3. We found the association in an interim analysis of a genome-wide nonsynonymous SNP (nsSNP) scan, and we validated it in a case-control collection and replicated it in an independent family collection. In 4,253 cases, 5,842 controls and 2,134 parent-child trio genotypes, the risk ratio for the minor allele of the nsSNP rs1990760 A → G (A946T) was 0.86 (95% confidence interval = 0.82–0.90) at P = 1.42 × 10−10.

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Acknowledgements

This work was funded by the Wellcome Trust and the Juvenile Diabetes Research Foundation International. We acknowledge the participation of all of the patients, controls subjects and family members. We thank the Human Biological Data Interchange and Diabetes UK for US and UK multiplex families, respectively; the Norwegian Study Group for Childhood Diabetes for the collection of the Norwegian families (D. Undlien and K. Ronningen). We acknowledge use of DNA from the 1958 British Birth Cohort collection (R. Jones, S. Ring, W. McArdle and M. Pembrey), funded by the Medical Research Council grant G0000934 and Wellcome Trust grant 068545/Z/02, and we thank D. Strachan and P. Burton for their help.

Author information

    • Deborah J Smyth
    •  & Jason D Cooper

    These authors contributed equally to this work.

Affiliations

  1. Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Addenbrooke's Hospital, Hills Road, Cambridge CB2 2XY, UK.

    • Deborah J Smyth
    • , Jason D Cooper
    • , Rebecca Bailey
    • , Sarah Field
    • , Oliver Burren
    • , Luc J Smink
    • , Neil M Walker
    • , David G Clayton
    •  & John A Todd

  2. Clinic of Diabetes, Institute of Diabetes, Nutrition and Metabolic Diseases 'N.Paulescu', Bucharest 79811, Romania.

    • Cristian Guja
    •  & Constantin Ionescu-Tirgoviste

  3. Department of Paediatrics, University of Cambridge, Addenbrooke's Hospital, Cambridge CB2 2XY, UK.

    • Barry Widmer
    •  & David B Dunger

  4. Department of Medical Genetics, Queen's University Belfast, Belfast City Hopsital, Belfast BT9 7AB, UK.

    • David A Savage

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Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to John A Todd.

Supplementary information

PDF files

  1. 1.

    Supplementary Fig. 1

    Genotyping clusters.

  2. 2.

    Supplementary Fig. 2

    Linkage disequilibrium across the IFIH1 region and odds ratios.

  3. 3.

    Supplementary Fig. 3

    Amino acid alignment of the IFIH1 region.

  4. 4.

    Supplementary Table 1

    The top ten nsSNP results from the interim analysis after attempting 2,029 cases and 1,755 control samples.

  5. 5.

    Supplementary Table 2

    SNPs identified from resequencing IFIH1 exons and 3 kb 5′ and 3′ of the gene in DNA samples from 32 CEPH individuals.

  6. 6.

    Supplementary Table 3

    Primer sequences for TaqMan assays and sequencing.

  7. 7.

    Supplementary Table 4

    Association analysis of common SNPs, listed in chromosome order, from the 2q24.3 region containing IFIH1 in type 1 diabetes cases and controls.

  8. 8.

    Supplementary Table 5

    Regression analysis of common SNPs from the region containing IFIH1 in type 1 diabetes cases and controls.

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DOI

https://doi.org/10.1038/ng1800

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