title: What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations.
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%)].
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.
authors.forename: Orestis A
authors.initials: OA
authors.lastname: Panagiotou
authors.forename: John P A
authors.initials: JP
authors.lastname: Ioannidis
mesh_terms: D036262:Empirical Research; D056726:Genetic Association Studies / Q000706:statistics & numerical data*; D055106:Genome-Wide Association Study / Q000592:standards*; D006801:Humans; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D012015:Reference Standards