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Weighting sequence variants based on their annotation increases power of whole-genome association studies

Nature Genetics volume 48, pages 314–317 (2016)Cite this article

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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.

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Figure 1: Enrichments of VEP annotations for all quantitative and binary phenotypes.
Figure 2: Enrichments for all quantitative and binary phenotypes.

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Acknowledgements

The authors thank all the participants in the study. We also thank the staff at the Patient Recruitment Center and the deCODE Genetics core facilities.

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Authors and Affiliations

  1. deCODE Genetics/Amgen, Inc., Reykjavik, Iceland

    Gardar Sveinbjornsson, Florian Zink, Sigurjón A Gudjonsson, Asmundur Oddson, Gísli Másson, Hilma Holm, Augustine Kong, Unnur Thorsteinsdottir, Patrick Sulem, Daniel F Gudbjartsson & Kari Stefansson

  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland

    Gardar Sveinbjornsson, Augustine Kong & Daniel F Gudbjartsson

  3. Department of Biology, Bioinformatics Centre, University of Copenhagen, Copenhagen, Denmark

    Anders Albrechtsen

  4. Division of Cardiology, Department of Internal Medicine, Landspitali, National University Hospital of Iceland, Reykjavik, Iceland

    Hilma Holm

  5. Faculty of Medicine, University of Iceland, Reykjavik, Iceland

    Unnur Thorsteinsdottir & Kari Stefansson

Authors
  1. Gardar Sveinbjornsson
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Contributions

The study was designed and results were interpreted by G.S., A.A., G.M., H.H., A.K., U.T., P.S., D.F.G. and K.S. G.S., A.A., F.Z., S.A.G., A.O., G.M., A.K., P.S. and D.F.G. performed the statistical and bioinformatics analyses. The manuscript was drafted by G.S., A.A., P.S., D.F.G. and K.S. All authors contributed to the final version of the manuscript.

Corresponding authors

Correspondence to Daniel F Gudbjartsson or Kari Stefansson.

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The authors declare no competing financial interests.

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Supplementary Tables 1–10 and Supplementary Note. (PDF 889 kb)

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Sveinbjornsson, G., Albrechtsen, A., Zink, F. et al. Weighting sequence variants based on their annotation increases power of whole-genome association studies. Nat Genet 48, 314–317 (2016). https://doi.org/10.1038/ng.3507

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