The result is that a true genome-wide study can be performed by actually genotyping as few as 300 000 to 1 million SNPs.7,8 However, because so many tests are being performed, it is necessary to obtain a very strongly significant P value to be sure that the result is really significant. This is known as “genome-wide significance” and the consensus is that this should be about 108 or less.9 Because the effects sizes of common variants are generally small, it is usually necessary to include a large number of subjects in the study in order to have the power

to detect a genome-wide significant P value (Figure 1.) Figure 1. The power to detect a Inhibitors,research,lifescience,medical causal learn more variant that is perfectly tagged by a genotyped marker (assuming dominant model, minor allele frequency=0.2, Inhibitors,research,lifescience,medical frequency of disease is 1% and equa numbers of cases and controls). To have a good chance of detecting a variant … Major discoveries with GWAS The

success of GWAS has been very variable for different disease areas. Some diseases have Inhibitors,research,lifescience,medical found common variants with very strong effects, and managed to track these down to the causal variant. An inspiring example is an intronic variant in BCL11A that was found in two GWAS studies to associate with fetal hemoglobin (HbF) levels in healthy adults,10, 11 and also to modify the presentation of (3-thalassemia, and associate with HbF levels in patients with sickle-cell disease.11 This finding was soon followed up with a functional study that showed that the variant associated with high HbF12 reduced the expression of BCL11A,13 and that reduction of BCL11A expression caused increase in levels of gamma-globin in Inhibitors,research,lifescience,medical adult human red blood progenitor cells, which led to increased Inhibitors,research,lifescience,medical levels of HbF13 These findings clearly suggest that BCL11A serves as an inhibitor of HbF production and that directed repression of BCL11A could be developed as a clinical tool to ameliorate the presentation

of thalassemias and sickle-cell disease. These findings in turn have led to further understanding of developmental and species-specific changes in globin regulation.14. On the less inspirational side, however, other diseases, like hypertension, have been thoroughly and carefully investigated using found huge numbers of patients and controls with very little progress.15 Here we outline some of the highest impact findings of GWAS and where (if anywhere) they have led us. As might be expected by the laws of natural selection, there are not many common genetic variants that confer a strong predisposition to common diseases. Such variants would be expected to have been selected against, and thus maintained at low population frequencies. However, there are some phenotypes that might be expected to have dodged the purifying effects of selection.