The Utility of Mouse Models in Post-GWAS Research

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Science  07 Dec 2012:
Vol. 338, Issue 6112, pp. 1301-1302
DOI: 10.1126/science.1231733

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Genome-wide association studies (GWAS) have discovered over 100 haplotype-tagging single-nucleotide polymorphisms (SNPs) that are associated with cancer risk. The small region between 128 and 129 Mb on the long arm of human chromosome 8 (Human Genome Build 37) notably contains a number of uncorrelated cancer predisposition SNPs (see the figure) (16). There are probably five or more different causal genetic variants in the region, and each is independently associated with the risk of one or more common cancers. Perhaps the most promiscuous variant is rs6983267—a common SNP in which guanine (G) is replaced by thymine (T)—at which the G allele is associated with increased risk of cancers of the prostate, large bowel, and thyroid. On page 1360 in this issue, Sur et al. (7) use a loss-of-function animal model to confirm that the region around the noncoding rs6983267 SNP identified using human GWAS probably has direct functional effects on tumorigenesis.