title: The (in)famous GWAS P-value threshold revisited and updated for low-frequency variants.
abstract: Genome-wide association studies (GWAS) have long relied on proposed statistical significance thresholds to be able to differentiate true positives from false positives. Although the genome-wide significance P-value threshold of 5 × 10(-8) has become a standard for common-variant GWAS, it has not been updated to cope with the lower allele frequency spectrum used in many recent array-based GWAS studies and sequencing studies. Using a whole-genome- and -exome-sequencing data set of 2875 individuals of European ancestry from the Genetics of Type 2 Diabetes (GoT2D) project and a whole-exome-sequencing data set of 13 000 individuals from five ancestries from the GoT2D and T2D-GENES (Type 2 Diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples) projects, we describe guidelines for genome- and exome-wide association P-value thresholds needed to correct for multiple testing, explaining the impact of linkage disequilibrium thresholds for distinguishing independent variants, minor allele frequency and ancestry characteristics. We emphasize the advantage of studying recent genetic isolate populations when performing rare and low-frequency genetic association analyses, as the multiple testing burden is diminished due to higher genetic homogeneity.
authors.affiliation: Department of Epidemiology Research, Statens Serum Institut, Copenhagen S, Denmark.|Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Malmo, Sweden.
authors.forename: João
authors.initials: J
authors.lastname: Fadista
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.
authors.forename: Alisa K
authors.initials: AK
authors.lastname: Manning
authors.affiliation: Program in Medical and Population Genetics, Broad Institute, Cambridge, MA, USA.|Center for Human Genetic Research, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.|Diabetes Research Center, Diabetes Unit, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA.|Department of Medicine, Harvard Medical School, Boston, MA, USA.
authors.forename: Jose C
authors.initials: JC
authors.lastname: Florez
authors.affiliation: Department of Clinical Sciences, Lund University Diabetes Centre, Lund University, Malmo, Sweden.|Institute for Molecular Medicine Finland FIMM, University of Helsinki, Helsinki, Finland.
authors.forename: Leif
authors.initials: L
authors.lastname: Groop
mesh_terms: D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics; D059472:Exome; D018740:Genetic Heterogeneity; D055106:Genome-Wide Association Study / Q000379:methods / Q000592:standards*; D006801:Humans; D015810:Linkage Disequilibrium; D059645:Mutation Rate