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Abstract

Loss-of-function mutations cause many mendelian diseases. Here we aimed to create a catalog of autosomal genes that are completely knocked out in humans by rare loss-of-function mutations. We sequenced the whole genomes of 2,636 Icelanders and imputed the sequence variants identified in this set into 101,584 additional chip-genotyped and phased Icelanders. We found a total of 6,795 autosomal loss-of-function SNPs and indels in 4,924 genes. Of the genotyped Icelanders, 7.7% are homozygotes or compound heterozygotes for loss-of-function mutations with a minor allele frequency (MAF) below 2% in 1,171 genes (complete knockouts). Genes that are highly expressed in the brain are less often completely knocked out than other genes. Homozygous loss-of-function offspring of two heterozygous parents occurred less frequently than expected (deficit of 136 per 10,000 transmissions for variants with MAF <2%, 95% confidence interval (CI) = 10–261).

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Acknowledgements

We thank all the participants in this study. This study was performed in collaboration with Illumina.

Author information

Author notes

    • Patrick Sulem
    •  & Hannes Helgason

    These authors contributed equally to this work.

Affiliations

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

    • Patrick Sulem
    • , Hannes Helgason
    • , Asmundur Oddson
    • , Hreinn Stefansson
    • , Sigurjon A Gudjonsson
    • , Florian Zink
    • , Eirikur Hjartarson
    • , Gunnar Th Sigurdsson
    • , Adalbjorg Jonasdottir
    • , Aslaug Jonasdottir
    • , Asgeir Sigurdsson
    • , Olafur Th Magnusson
    • , Augustine Kong
    • , Agnar Helgason
    • , Hilma Holm
    • , Unnur Thorsteinsdottir
    • , Gisli Masson
    • , Daniel F Gudbjartsson
    •  & Kari Stefansson
  2. School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.

    • Hannes Helgason
    • , Augustine Kong
    •  & Daniel F Gudbjartsson
  3. Department of Anthropology, University of Iceland, Reykjavik, Iceland.

    • Agnar Helgason
  4. Department of Internal Medicine, Landspitali The National University Hospital of Iceland, Reykjavik, Iceland.

    • Hilma Holm
  5. Faculty of Medicine, University of Iceland, Reykjavik, Iceland.

    • Unnur Thorsteinsdottir
    •  & Kari Stefansson

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Contributions

P.S., H. Helgason, A.O., U.T., G.M., D.F.G. and K.S. designed the experiment. H.S., H. Holm and U.T. collected the samples. Adalbjorg Jonasdottir, Aslaug Jonasdottir, A.S. and O.T.M. performed the sequencing experiments. P.S., H. Helgason, S.A.G., F.Z., E.H., G.T.S., A.K., G.M. and D.F.G. analyzed the data. P.S., H. Helgason, A.H., D.F.G. and K.S. wrote the first draft of the manuscript. All authors contributed to the final version of the manuscript.

Competing interests

The authors affiliated with deCODE Genetics are employed by the company: P.S., H. Helgason A.O., H.S., S.A.G., F.Z., E.H., G.T.S., Adalbjorg Jonasdottir, Aslaug Jonasdottir, A.S., O.T.M., A.K., A.H., H. Holm, U.T., G.M., D.F.G. and K.S.

Corresponding authors

Correspondence to Patrick Sulem or Kari Stefansson.

Integrated supplementary information

Supplementary information

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    Supplementary Text and Figures

    Supplementary Figures 1–7, Supplementary Note and Supplementary Tables 1–3 and 5–11.

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    Supplementary Table 4

    The observed list of 6,795 LoF mutations in 4,924 genes.

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DOI

https://doi.org/10.1038/ng.3243

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