What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations

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 ^-8. If the seven associations that did not reach P ≤ 5 × 10 ^-8 when additional data were considered are assumed to have been false-positives, the false-discovery rate for borderline associations is estimated to be 27% [95% confidence interval (CI) 12-48%]. For five associations, the current P-value is > 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. Published by Oxford University Press on behalf of the International Epidemiological Association