Genome-wide significance explained

In genome-wide association studies, genome-wide significance (abbreviated GWS) is a specific threshold for determining the statistical significance of a reported association between a given single-nucleotide polymorphism (SNP) and a given trait. The most commonly accepted threshold is p < 5 × 10−8, which is based on performing a Bonferroni correction for all the independent common SNPs across the human genome.[1] If a p-value is found to be lower than this threshold in a genome-wide association study, the null hypothesis of no true SNP-association will typically be rejected.[2] However, there has been some criticism of this threshold, with a 2012 study suggesting that a significant number of associations with p-values just above this threshold are genuine, replicable associations. The authors of this study concluded that their finding "...suggests a possible relaxation in the current GWS threshold."[3] More recently, it has been suggested that the conventional threshold should be modified to take into account the increasing prevalence of low-frequency genetic variants in genome-wide association studies.[4]

Notes and References

  1. Xu . ChangJiang . Tachmazidou . Ioanna . Walter . Klaudia . Ciampi . Antonio . Zeggini . Eleftheria . Celia Greenwood. Greenwood . Celia M. T. . the UK10K Consortium . April 2014 . Estimating Genome-Wide Significance for Whole-Genome Sequencing Studies: Genome-Wide Significance for Rare Variants . Genetic Epidemiology . en . 38 . 4 . 281–290 . 10.1002/gepi.21797 . 4489336 . 24676807.
  2. Roeder . Kathryn . Wasserman . Larry . November 2009 . Genome-Wide Significance Levels and Weighted Hypothesis Testing . Statistical Science. 24 . 4 . 398–413 . 10.1214/09-STS289 . 0883-4237 . 2920568 . 20711421.
  3. Panagiotou . Orestis A . Ioannidis . John P A . for the Genome-Wide Significance Project . February 2012 . What should the genome-wide significance threshold be? Empirical replication of borderline genetic associations . International Journal of Epidemiology . en . 41 . 1 . 273–286 . 10.1093/ije/dyr178 . 22253303 . 0300-5771. free .
  4. Fadista . João . Manning . Alisa K. . Florez . Jose C. . Groop . Leif . August 2016 . The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants . European Journal of Human Genetics . 24 . 8 . 1202–1205 . 10.1038/ejhg.2015.269 . 1476-5438 . 4970684 . 26733288.

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