Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality-Reference-Cited by-同舟云学术

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

Published:2023-06-10 Issue:1 Volume:14 Page:
ISSN:2041-1723
Container-title:Nature Communications
language:en
Short-container-title:Nat Commun

Author:

Oddsson Asmundur^ORCID,Sulem Patrick^ORCID,Sveinbjornsson Gardar^ORCID,Arnadottir Gudny A.^ORCID,Steinthorsdottir Valgerdur^ORCID,Halldorsson Gisli H.^ORCID,Atlason Bjarni A.^ORCID,Oskarsson Gudjon R.^ORCID,Helgason Hannes,Nielsen Henriette Svarre^ORCID,Westergaard David^ORCID,Karjalainen Juha M.,Katrinardottir Hildigunnur,Fridriksdottir Run,Jensson Brynjar O.^ORCID,Tragante Vinicius^ORCID,Ferkingstad Egil^ORCID,Jonsson Hakon^ORCID,Gudjonsson Sigurjon A.,Beyter Doruk,Moore Kristjan H. S.^ORCID,Thordardottir Helga B.,Kristmundsdottir Snaedis^ORCID,Stefansson Olafur A.,Rantapää-Dahlqvist Solbritt^ORCID,Sonderby Ida Elken^ORCID,Didriksen Maria^ORCID,Stridh Pernilla^ORCID,Haavik Jan^ORCID,Tryggvadottir Laufey^ORCID,Frei Oleksandr,Walters G. Bragi^ORCID,Kockum Ingrid^ORCID,Hjalgrim Henrik,Olafsdottir Thorunn A.^ORCID,Selbaek Geir^ORCID,Nyegaard Mette^ORCID,Erikstrup Christian^ORCID,Brodersen Thorsten^ORCID,Saevarsdottir Saedis^ORCID,Olsson Tomas,Nielsen Kaspar Rene,Haraldsson Asgeir,Bruun Mie Topholm^ORCID,Hansen Thomas Folkmann,Brunak Søren,Nielsen Kasper Rene,Brun Mie Topholm,Stefánsson Hreinn,Þorsteinsdóttir Unnur,Steingrimsdottir Thora,Jacobsen Rikke Louise^ORCID,Lie Rolv T.^ORCID,Djurovic Srdjan^ORCID,Alfredsson Lars^ORCID,Lopez de Lapuente Portilla Aitzkoa,Brunak Soren^ORCID,Melsted Pall,Halldorsson Bjarni V.^ORCID,Saemundsdottir Jona,Magnusson Olafur Th.,Padyukov Leonid^ORCID,Banasik Karina^ORCID,Rafnar Thorunn^ORCID,Askling Johan,Klareskog Lars^ORCID,Pedersen Ole Birger^ORCID,Masson Gisli,Havdahl Alexandra^ORCID,Nilsson Bjorn^ORCID,Andreassen Ole A.^ORCID,Daly Mark,Ostrowski Sisse Rye^ORCID,Jonsdottir Ingileif^ORCID,Stefansson Hreinn,Holm Hilma^ORCID,Helgason Agnar,Thorsteinsdottir Unnur,Stefansson Kari^ORCID,Gudbjartsson Daniel F.^ORCID,

Abstract

AbstractGenotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. To explore genetic causes of recessive lethality, we searched for sequence variants with deficit of homozygosity among 1.52 million individuals from six European populations. In this study, we identified 25 genes harboring protein-altering sequence variants with a strong deficit of homozygosity (10% or less of predicted homozygotes). Sequence variants in 12 of the genes cause Mendelian disease under a recessive mode of inheritance, two under a dominant mode, but variants in the remaining 11 have not been reported to cause disease. Sequence variants with a strong deficit of homozygosity are over-represented among genes essential for growth of human cell lines and genes orthologous to mouse genes known to affect viability. The function of these genes gives insight into the genetics of intrauterine lethality. We also identified 1077 genes with homozygous predicted loss-of-function genotypes not previously described, bringing the total set of genes completely knocked out in humans to 4785.

Publisher

Springer Science and Business Media LLC

Subject

General Physics and Astronomy,General Biochemistry, Genetics and Molecular Biology,General Chemistry,Multidisciplinary

Link

https://www.nature.com/articles/s41467-023-38951-2.pdf

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