title: Weighting sequence variants based on their annotation increases power of whole-genome association studies.
abstract: The consensus approach to genome-wide association studies (GWAS) has been to assign equal prior probability of association to all sequence variants tested. However, some sequence variants, such as loss-of-function and missense variants, are more likely than others to affect protein function and are therefore more likely to be causative. Using data from whole-genome sequencing of 2,636 Icelanders and the association results for 96 quantitative and 123 binary phenotypes, we estimated the enrichment of association signals by sequence annotation. We propose a weighted Bonferroni adjustment that controls for the family-wise error rate (FWER), using as weights the enrichment of sequence annotations among association signals. We show that this weighted adjustment increases the power to detect association over the standard Bonferroni correction. We use the enrichment of associations by sequence annotation we have estimated in Iceland to derive significance thresholds for other populations with different numbers and combinations of sequence variants.
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Gardar
authors: G
authors: Sveinbjornsson
authors: Bioinformatics Centre, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
authors: Anders
authors: http://orcid.org/0000-0001-7306-031X
authors: A
authors: Albrechtsen
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Florian
authors: F
authors: Zink
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Sigurjón A
authors: SA
authors: Gudjonsson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Asmundur
authors: A
authors: Oddson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Gísli
authors: G
authors: Másson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland.
authors: Hilma
authors: H
authors: Holm
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Augustine
authors: A
authors: Kong
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Patrick
authors: http://orcid.org/0000-0001-7123-6123
authors: P
authors: Sulem
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Daniel F
authors: http://orcid.org/0000-0002-5222-9857
authors: DF
authors: Gudbjartsson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.|Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Kari
authors: K
authors: Stefansson
mesh_terms: D055106:Genome-Wide Association Study / Q000379:methods* / Q000706:statistics & numerical data; D006801:Humans; D007055:Iceland / Q000453:epidemiology; D058977:Molecular Sequence Annotation; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D017422:Sequence Analysis, DNA