Identification of a large set of rare complete human knockouts

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

144 Citations (Scopus)


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).

Original languageEnglish
Pages (from-to)448-452
Number of pages5
JournalNature Genetics
Issue number5
Publication statusPublished - 30 May 2015

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© 2015 Nature America, Inc.


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