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Population-wide generalizability of genome-wide discovered associations.

JNCI | Editorials 1297 Genome-wide association studies (GWAS) have started revealing hundreds of associations between genetic variants and phenotypes ( 1 , 2 ). Most associations have robust statistical support in the populations where they have been examined. However, almost all GWAS published to date were performed in populations of European ancestry, and the replication efforts in the original publications also focused primarily on similar populations. Are these discovered associations relevant for populations of different ancestry? In this issue, a study by Yamada et al. ( 3 ) evaluated in Japanese participants 23 single-nucleotide polymorphisms (SNPs) that had been identifi ed in the GWAS era. Of those, 16 had emerged originally from studies of European descent populations, two from African descent populations, and fi ve from studies addressing diverse populations. Seven of these 23 SNPs (fi ve independent loci) showed nominally statistically signifi cant associations ( P < .05) with prostate cancer risk in the Japanese population. The other 16 SNPs were not associated with prostate cancer risk, and in fi ve of those, the point estimates of the odds ratios (ORs) were in opposite direction than previously described. Do these results herald extensive nonreplication vs the original discoveries? Not necessarily. One can estimate the power of Yamada et al. (311 case patients and 1035 control subjects) to detect ORs similar to those previously found, given the allele frequencies observed in the Japanese population. I used the per-allele ORs found in European descent populations ( 1 , 4 , 5 ) in 21 previously evaluated SNPs for a comparison against the Japanese data ( Figure 1 ). Estimated power ( 6 ) at alpha value of .05 ranges from almost 0% for rs4962416, which has a 1% risk allele frequency in the Japanese population, to practically 100% for rs16901979, for which the previously proposed OR was large (1.79) and the risk allele frequency in the Japanese population is 19%. If we sum the power estimates for all SNPs to detect the respective ORs previously seen in European descent participants, we can estimate that if ORs were identical in the Japanese population,