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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.

Original publication

DOI

10.1126/science.1167728

Type

Journal article

Journal

Science

Publication Date

17/04/2009

Volume

324

Pages

387 - 389

Keywords

Base Sequence, Case-Control Studies, Codon, Nonsense, DEAD-box RNA Helicases, Diabetes Mellitus, Type 1, Gene Frequency, Genetic Predisposition to Disease, Genetic Variation, Genome-Wide Association Study, Humans, Interferon-Induced Helicase, IFIH1, Linkage Disequilibrium, Molecular Sequence Data, Polymorphism, Single Nucleotide, RNA Splice Sites, Risk, Risk Factors, Sequence Analysis, DNA