Empirical estimation of genome-wide significance thresholds based on the 1000 Genomes Project data set.
To assess the statistical significance of associations between variants and traits, genome-wide association studies (GWAS) should employ an appropriate threshold that accounts for the massive burden of multiple testing in the study. Although most studies in the current literature commonly set a genome-wide significance threshold at the level of P=5.0 × 10-8, the adequacy of this value for respective populations has not been fully investigated. To empirically estimate thresholds for different ancestral populations, we conducted GWAS simulations using the 1000 Genomes Phase 3 data set for Africans (AFR), Europeans (EUR), Admixed Americans (AMR), East Asians (EAS) and South Asians (SAS). The estimated empirical genome-wide significance thresholds were Psig=3.24 × 10-8(AFR), 9.26 × 10-8(EUR), 1.83 × 10-7(AMR), 1.61 × 10-7(EAS) and 9.46 × 10-8(SAS). We additionally conducted trans-ethnic meta-analyses across all populations (ALL) and all populations except for AFR (ΔAFR), which yielded Psig=3.25 × 10-8(ALL) and 4.20 × 10-8(ΔAFR). Our results indicate that the current threshold (P=5.0 × 10-8) is overly stringent for all ancestral populations except for Africans; however, we should employ a more stringent threshold when conducting a meta-analysis, regardless of the presence of African samples.
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.
Masahiro
M
Kanai
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Bioresource Research Center, Tokyo Medical and Dental University, Tokyo, Japan.
Toshihiro
http://orcid.org/0000-0001-6201-9784
T
Tanaka
Department of Human Genetics and Disease Diversity, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.|Department of Statistical Genetics, Osaka University Graduate School of Medicine, Osaka, Japan.
Yukinori
Y
Okada
D003198:Computer Simulation; D066264:Datasets as Topic; D005006:Ethnicity / Q000235:genetics; D005828:Genetics, Population / Q000379:methods; D055106:Genome-Wide Association Study / Q000379:methods; D023281:Genomics / Q000379:methods; D006801:Humans; D015810:Linkage Disequilibrium; D015201:Meta-Analysis as Topic; D008957:Models, Genetic