title: Identification of a large set of rare complete human knockouts.
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).
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Patrick
authors: 0000000171236123
authors: P
authors: Sulem
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Hannes
authors: H
authors: Helgason
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Asmundur
authors: A
authors: Oddson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Hreinn
authors: H
authors: Stefansson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Sigurjon A
authors: SA
authors: Gudjonsson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Florian
authors: F
authors: Zink
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Eirikur
authors: E
authors: Hjartarson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Gunnar Th
authors: GT
authors: Sigurdsson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Adalbjorg
authors: A
authors: Jonasdottir
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Aslaug
authors: A
authors: Jonasdottir
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Asgeir
authors: A
authors: Sigurdsson
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Olafur Th
authors: OT
authors: Magnusson
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Augustine
authors: A
authors: Kong
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Anthropology, University of Iceland, Reykjavik, Iceland.
authors: Agnar
authors: A
authors: Helgason
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Department of Internal Medicine, Landspitali The National University Hospital of Iceland, Reykjavik, Iceland.
authors: Hilma
authors: H
authors: Holm
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Unnur
authors: U
authors: Thorsteinsdottir
authors: deCODE Genetics/Amgen, Inc., Reykjavik, Iceland.
authors: Gisli
authors: G
authors: Masson
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] School of Engineering and Natural Sciences, University of Iceland, Reykjavik, Iceland.
authors: Daniel F
authors: 0000000252229857
authors: DF
authors: Gudbjartsson
authors: 1] deCODE Genetics/Amgen, Inc., Reykjavik, Iceland. [2] Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
authors: Kari
authors: K
authors: Stefansson
mesh_terms: D001921:Brain / Q000378:metabolism; D005260:Female; D015870:Gene Expression; D005787:Gene Frequency; D063990:Gene Ontology; D015894:Genome, Human; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D054643:INDEL Mutation; D008297:Male; D016366:Open Reading Frames; D009928:Organ Specificity; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA