The problem of identifying the functional variant is well illustrated by the extensive studies on the undoubtedly significant association of SNPs at 8q24 with both colorectal and prostate cancer26-28. For colorectal cancer, the highest overall OR was 1.22 and the estimated population attributable risk (PAR) around 20% (ref. 26). Nevertheless, extensive sequencing around the most associated SNPs has not yet given any real clues as to which is the causal variation. The causal basis for the rare variants described for colorectal adenomas23 was, on the other hand, quite unequivocal. However, highly suggestive causal common variants have been identified for both Crohn's disease29 and T1D (ref. 30). This is in keeping with the idea that common variants with higher ORs may be those that have been subject to comparatively recent natural selection, such as variants in HLA and other immune function genes in relation to infections, and perhaps the diabetes-associated variants in relation to available food supplies.
