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BACKGROUND: Robust replication is a sine qua non for the rigorous documentation of proposed associations in the genome-wide association (GWA) setting. Currently, associations of common variants reaching P ≤ 5 × 10(-8) are considered replicated. However, there is some ambiguity about the most suitable threshold for claiming genome-wide significance. METHODS: We defined as 'borderline' associations those with P > 5 × 10(-8) and P ≤ 1 × 10(-7). The eligible associations were retrieved using the 'Catalog of Published Genome-Wide Association Studies'. For each association we assessed whether it reached P ≤ 5 × 10(-8) with inclusion of additional data from subsequent GWA studies. RESULTS: Thirty-four eligible genotype-phenotype associations were evaluated with data and clarifications contributed from diverse investigators. Replication data from subsequent GWA studies could be obtained for 26 of them. Of those, 19 associations (73%) reached P ≤ 5 × 10(-8) for the same or a related trait implicating either the exact same allele or one in very high linkage disequilibrium and 17 reached P 10(-6) corresponding false-discovery rate 19% (95% CI 7-39%). CONCLUSION: A substantial proportion, but not all, of the associations with borderline genome-wide significance represent replicable, possibly genuine associations. Our empirical evaluation suggests a possible relaxation in the current GWS threshold.
Panagiotou et al. (2011) studied this question.