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

Ásmundur Oddsson(deCODE Genetics (Iceland)), Patrick Sulem(deCODE Genetics (Iceland)), Garðar Sveinbjörnsson(deCODE Genetics (Iceland)), Gudny A. Arnadottir(deCODE Genetics (Iceland)), Valgerður Steinthórsdóttir(deCODE Genetics (Iceland)), Gísli H. Halldórsson(deCODE Genetics (Iceland)), Bjarni A. Atlason(deCODE Genetics (Iceland)), Gudjon R. Oskarsson(deCODE Genetics (Iceland)), Hannes Helgason(deCODE Genetics (Iceland)), Henriette Svarre Nielsen(University of Copenhagen), David Westergaard(University of Copenhagen), Juha Karjalainen(University of Helsinki), Hildigunnur Katrínardóttir(deCODE Genetics (Iceland)), Rún Friðriksdóttir(deCODE Genetics (Iceland)), Brynjar Ö. Jensson(deCODE Genetics (Iceland)), Vinicius Tragante(deCODE Genetics (Iceland)), Egil Ferkingstad(deCODE Genetics (Iceland)), Hákon Jónsson(deCODE Genetics (Iceland)), Sigurjón A. Guðjónsson(deCODE Genetics (Iceland)), Doruk Beyter(deCODE Genetics (Iceland)), Kristjan H. S. Moore(deCODE Genetics (Iceland)), Helga B. Thordardottir(deCODE Genetics (Iceland)), Snædís Kristmundsdóttir(deCODE Genetics (Iceland)), Ólafur Andri Stefánsson(deCODE Genetics (Iceland)), Solbritt Rantapää‐Dahlqvist(Umeå University), Ida E. Sønderby(Oslo University Hospital), Maria Didriksen(Copenhagen University Hospital), Pernilla Stridh(Karolinska University Hospital), Jan Haavik(Haukeland University Hospital), Laufey Tryggvadóttír(University of Iceland), Oleksandr Frei(Oslo University Hospital), G. Bragi Walters(deCODE Genetics (Iceland)), Ingrid Kockum(Karolinska University Hospital), Henrik Hjalgrim(Statens Serum Institut), Thorunn A. Olafsdottir(deCODE Genetics (Iceland)), Geir Selbæk(Oslo University Hospital), Mette Nyegaard(Aalborg University), Christian Erikstrup(Aarhus University), Thorsten Brodersen(Zealand University Hospital Køge), Saedís Saevarsdóttir(deCODE Genetics (Iceland)), Tomas Olsson(Karolinska University Hospital), Kaspar René Nielsen(Aalborg University Hospital), Ásgeir Haraldsson(University of Iceland), Mie Topholm Bruun(Odense University Hospital), Thomas Folkmann Hansen(University of Copenhagen), Søren Brunak(University of Copenhagen), Kasper Nielsen(Aalborg University Hospital), Mie Topholm Brun(Odense University Hospital), Hreinn Stefánsson(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Þóra Steingrímsdóttir(University of Iceland), Rikke Louise Jacobsen(Copenhagen University Hospital), Rolv T. Lie(Norwegian Institute of Public Health), Srdjan Djurovic(Oslo University Hospital), Lars Alfredsson(Karolinska Institutet), Aitzkoa Lopez de Lapuente Portilla(Lund University), Søren Brunak(University of Copenhagen), Páll Melsted(deCODE Genetics (Iceland)), Bjarni V. Halldórsson(Reykjavík University), Jona Saemundsdottir(deCODE Genetics (Iceland)), Ólafur Þ. Magnússon(deCODE Genetics (Iceland)), Leonid Padyukov(Karolinska Institutet), Karina Banasik(University of Copenhagen), Þórunn Rafnar(deCODE Genetics (Iceland)), Johan Askling(Karolinska Institutet), Lars Klareskog(Karolinska Institutet), Ole Birger Pedersen(University of Copenhagen), Gísli Másson(deCODE Genetics (Iceland)), Alexandra Havdahl(Norwegian Institute of Public Health), Björn Nilsson(Lund University), Ole A. Andreassen(Oslo University Hospital), Mark J. Daly(Broad Institute), Sisse Rye Ostrowski(University of Copenhagen), Ingileif Jónsdóttir(deCODE Genetics (Iceland)), Hreinn Stefánsson(deCODE Genetics (Iceland)), Hilma Hólm(deCODE Genetics (Iceland)), Agnar Helgason(deCODE Genetics (Iceland)), Unnur Þorsteinsdóttir(deCODE Genetics (Iceland)), Kāri Stefánsson(deCODE Genetics (Iceland)), Daníel F. Guðbjartsson(Reykjavík University)
Nature Communications
June 10, 2023
10.1038/s41467-023-38951-2
Cited by 14Open Access
Full Text

Abstract

Genotypes 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.

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