| Titre : | What should the genome-wide significance threshold be ? Empirical replication of borderline genetic associations. (2012) |
| Auteurs : | Orestis-A PANAGIOTOU ; IOANNIDIS (John-Pa) : GRC. Biomedical Research Institute. Foundation for Research and Technology-Hellas. Ioannina. |
| Type de document : | Article |
| Dans : | International journal of epidemiology (vol. 41, n° 1, 2012) |
| Pagination : | 273-286 |
| Langues: | Anglais |
| Mots-clés : | Génome ; Seuil ; Génétique ; Association ; Taux |
| Résumé : | [BDSP. Notice produite par INIST-CNRS nR0x9FIs. Diffusion soumise à autorisation]. 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 x 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 x 10-8 and P<=1 x 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 x 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 x 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 x 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. |
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