The first well–known suggestion for a genomewide significance threshold for association was by Risch and Merikangas [1996]. They assumed a gene-centric study of 100,000 genes, with an average of five SNPs tested in each gene, leading to a Bonferroni significance threshold of 5 × 10−8 for one–sided tests of each allele. Although these assumptions are now obsolete, this threshold has proved remarkably durable, and valid in the sense that, to our knowledge, no association reported as exceeding it has proved a false positive. Another estimate for a gene-centric study assumed 30,000 genes, with 10 genes having normally distributed effects, leading to a threshold of 1 × 10−6 for a genewide test [Clayton, 2003; Thomas and Clayton, 2004].
