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.
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Supplementary information
Supplementary Fig. 1
Genotyping clusters. (PDF 121 kb)
Supplementary Fig. 2
Linkage disequilibrium across the IFIH1 region and odds ratios. (PDF 500 kb)
Supplementary Fig. 3
Amino acid alignment of the IFIH1 region. (PDF 182 kb)
Supplementary Table 1
The top ten nsSNP results from the interim analysis after attempting 2,029 cases and 1,755 control samples. (PDF 52 kb)
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. (PDF 30 kb)
Supplementary Table 3
Primer sequences for TaqMan assays and sequencing. (PDF 69 kb)
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. (PDF 32 kb)
Supplementary Table 5
Regression analysis of common SNPs from the region containing IFIH1 in type 1 diabetes cases and controls. (PDF 70 kb)
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Smyth, D., Cooper, J., Bailey, R. et al. A genome-wide association study of nonsynonymous SNPs identifies a type 1 diabetes locus in the interferon-induced helicase (IFIH1) region. Nat Genet 38, 617–619 (2006). https://doi.org/10.1038/ng1800
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DOI: https://doi.org/10.1038/ng1800
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