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

Orestis A. Panagiotou, John P.A. Ioannidis, Joel N. Hirschhorn, Goncalo R. Abecasis, Timothy M. Frayling, Mark I. McCarthy, Cecilia M. Lindgren, Terri H. Beaty, Nicholas Eriksson, Constantin Polychronakos, Sekar Kathirensan, Robert M. Plenge, Richard Spritz, Haydeh Payami, Eden R. Martin, Jeffery Vance, Wen Hui Su, Yu Sun Chang, Jin Xin Bei, Yi Xin ZengGuillaume Paré, Stephen V. Faraone, Benjamine Neale, Richard J. Anney, Bryan J. Traynor, André Scherag, Johannes Hebebrand, Anke Hinney, Philippe Froguel, David Meyre, Stephen J. Chanock, Wang Kesheng

Research output: Contribution to journalArticle

Abstract

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

Original languageEnglish (US)
Article numberdyr178
Pages (from-to)273-286
Number of pages14
JournalInternational journal of epidemiology
Volume41
Issue number1
DOIs
StatePublished - Feb 1 2012

Keywords

  • False-discovery rate
  • Genome-wide association study
  • Genome-wide significance
  • Meta-analysis
  • Replication

ASJC Scopus subject areas

  • Epidemiology

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    Panagiotou, O. A., Ioannidis, J. P. A., Hirschhorn, J. N., Abecasis, G. R., Frayling, T. M., McCarthy, M. I., Lindgren, C. M., Beaty, T. H., Eriksson, N., Polychronakos, C., Kathirensan, S., Plenge, R. M., Spritz, R., Payami, H., Martin, E. R., Vance, J., Su, W. H., Chang, Y. S., Bei, J. X., ... Kesheng, W. (2012). What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations. International journal of epidemiology, 41(1), 273-286. [dyr178]. https://doi.org/10.1093/ije/dyr178