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

Deborah J Smyth^1, 5, Jason D Cooper^1, 5, Rebecca Bailey¹, Sarah Field¹, Oliver Burren¹, Luc J Smink¹, Cristian Guja², Constantin Ionescu-Tirgoviste², Barry Widmer³, David B Dunger³, David A Savage⁴, Neil M Walker¹, David G Clayton¹ & John A Todd¹

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.

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

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

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

⁵  These authors contributed equally to this work.

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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