Genome-wide significance

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]

References
  1. Xu, ChangJiang; Tachmazidou, Ioanna; Walter, Klaudia; Ciampi, Antonio; Zeggini, Eleftheria; 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. 38 (4): 281–290. doi:10.1002/gepi.21797. PMC 4489336. PMID 24676807.
  2. Roeder, Kathryn; Wasserman, Larry (November 2009). "Genome-Wide Significance Levels and Weighted Hypothesis Testing". Statistical Science. 24 (4): 398–413. doi:10.1214/09-STS289. ISSN 0883-4237. PMC 2920568. PMID 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. 41 (1): 273–286. doi:10.1093/ije/dyr178. ISSN 0300-5771. PMID 22253303.
  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. doi:10.1038/ejhg.2015.269. ISSN 1476-5438. PMC 4970684. PMID 26733288.


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