Saturday, March 07, 2009

Discovery of rare variants in regions identified by GWASs

P-ter at GNXP and Dan at Genetic Future discuss what seems to be an interesting and important recently published paper in Science (abstract below) that finds four rare variants with larger-than-usual effects for Type-1 Diabetes. The last line of the abstract pretty much says it all. The evolutionary interpretation is of course very interesting, especially since the rare variants reduce risk. Dan talks about this.

Rare Variants of IFIH1, a Gene Implicated in Antiviral Responses, Protect Against Type 1 Diabetes
Sergey Nejentsev, Neil Walker , David Riches, Michael Egholm, John A. Todd
Science DOI: 10.1126/science.1167728
Abstract: Genome-wide association studies (GWAS) are widely 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 ten candidate genes in pools of DNA from 480 patients and 480 controls and tested their disease association in over 30,000 subjects. We discovered four rare variants that lowered T1D risk independently of each other (OR = 0.51 – 0.74; P = 1.3 x 10-3 – 2.1 x 10-16) in IFIH1, a gene located in a region previously associated with T1D by GWAS. These variants are predicted to alter the expression and structure of IFIH1 (MDA5), a cytoplasmic helicase that mediates induction of interferon response to viral RNA. This firmly establishes the role of IFIH1 in T1D and demonstrates that resequencing studies can pinpoint disease-causing genes in genomic regions initially identified by GWAS.

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