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Originally published in Science Express on 5 March 2009
Science 17 April 2009:
Vol. 324. no. 5925, pp. 387 - 389
DOI: 10.1126/science.1167728
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Reports

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes

Sergey Nejentsev,1,2* Neil Walker,1 David Riches,3 Michael Egholm,3 John A. Todd1

Genome-wide association studies (GWASs) are regularly used to map genomic regions contributing to common human diseases, but they often do not identify the precise causative genes and sequence variants. To identify causative type 1 diabetes (T1D) variants, we resequenced exons and splice sites of 10 candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 participants. We discovered four rare variants that lowered T1D risk independently of each other (odds ratio = 0.51 to 0.74; P = 1.3 x 10–3 to 2.1 x 10–16) in IFIH1 (interferon induced with helicase C domain 1), a gene located in a region previously associated with T1D by GWASs. These variants are predicted to alter the expression and structure of IFIH1 [MDA5 (melanoma differentiation-associated protein 5)], a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This finding firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWASs.

1 Juvenile Diabetes Research Foundation/Wellcome Trust Diabetes and Inflammation Laboratory, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, CB2 0XY, UK.
2 Department of Medicine, University of Cambridge, CB2 2QQ, UK.
3 454 Life Sciences, Branford, CT 06405, USA.

* To whom the correspondence should be addressed. E-mail: sn262{at}cam.ac.uk

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