Nature Communications (Jun 2023)
Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
- Asmundur Oddsson,
- Patrick Sulem,
- Gardar Sveinbjornsson,
- Gudny A. Arnadottir,
- Valgerdur Steinthorsdottir,
- Gisli H. Halldorsson,
- Bjarni A. Atlason,
- Gudjon R. Oskarsson,
- Hannes Helgason,
- Henriette Svarre Nielsen,
- David Westergaard,
- Juha M. Karjalainen,
- Hildigunnur Katrinardottir,
- Run Fridriksdottir,
- Brynjar O. Jensson,
- Vinicius Tragante,
- Egil Ferkingstad,
- Hakon Jonsson,
- Sigurjon A. Gudjonsson,
- Doruk Beyter,
- Kristjan H. S. Moore,
- Helga B. Thordardottir,
- Snaedis Kristmundsdottir,
- Olafur A. Stefansson,
- Solbritt Rantapää-Dahlqvist,
- Ida Elken Sonderby,
- Maria Didriksen,
- Pernilla Stridh,
- Jan Haavik,
- Laufey Tryggvadottir,
- Oleksandr Frei,
- G. Bragi Walters,
- Ingrid Kockum,
- Henrik Hjalgrim,
- Thorunn A. Olafsdottir,
- Geir Selbaek,
- Mette Nyegaard,
- Christian Erikstrup,
- Thorsten Brodersen,
- Saedis Saevarsdottir,
- Tomas Olsson,
- Kaspar Rene Nielsen,
- Asgeir Haraldsson,
- Mie Topholm Bruun,
- Thomas Folkmann Hansen,
- DBDS Genomic Consortium,
- Thora Steingrimsdottir,
- Rikke Louise Jacobsen,
- Rolv T. Lie,
- Srdjan Djurovic,
- Lars Alfredsson,
- Aitzkoa Lopez de Lapuente Portilla,
- Soren Brunak,
- Pall Melsted,
- Bjarni V. Halldorsson,
- Jona Saemundsdottir,
- Olafur Th. Magnusson,
- Leonid Padyukov,
- Karina Banasik,
- Thorunn Rafnar,
- Johan Askling,
- Lars Klareskog,
- Ole Birger Pedersen,
- Gisli Masson,
- Alexandra Havdahl,
- Bjorn Nilsson,
- Ole A. Andreassen,
- Mark Daly,
- Sisse Rye Ostrowski,
- Ingileif Jonsdottir,
- Hreinn Stefansson,
- Hilma Holm,
- Agnar Helgason,
- Unnur Thorsteinsdottir,
- Kari Stefansson,
- Daniel F. Gudbjartsson
Affiliations
- Asmundur Oddsson
- deCODE genetics/Amgen, Inc.
- Patrick Sulem
- deCODE genetics/Amgen, Inc.
- Gardar Sveinbjornsson
- deCODE genetics/Amgen, Inc.
- Gudny A. Arnadottir
- deCODE genetics/Amgen, Inc.
- Valgerdur Steinthorsdottir
- deCODE genetics/Amgen, Inc.
- Gisli H. Halldorsson
- deCODE genetics/Amgen, Inc.
- Bjarni A. Atlason
- deCODE genetics/Amgen, Inc.
- Gudjon R. Oskarsson
- deCODE genetics/Amgen, Inc.
- Hannes Helgason
- deCODE genetics/Amgen, Inc.
- Henriette Svarre Nielsen
- Deptartment of Obstetrics and Gynecology, Copenhagen University Hospital
- David Westergaard
- Deptartment of Obstetrics and Gynecology, Copenhagen University Hospital
- Juha M. Karjalainen
- Institute for Molecular Medicine, Finland, University of Helsinki
- Hildigunnur Katrinardottir
- deCODE genetics/Amgen, Inc.
- Run Fridriksdottir
- deCODE genetics/Amgen, Inc.
- Brynjar O. Jensson
- deCODE genetics/Amgen, Inc.
- Vinicius Tragante
- deCODE genetics/Amgen, Inc.
- Egil Ferkingstad
- deCODE genetics/Amgen, Inc.
- Hakon Jonsson
- deCODE genetics/Amgen, Inc.
- Sigurjon A. Gudjonsson
- deCODE genetics/Amgen, Inc.
- Doruk Beyter
- deCODE genetics/Amgen, Inc.
- Kristjan H. S. Moore
- deCODE genetics/Amgen, Inc.
- Helga B. Thordardottir
- deCODE genetics/Amgen, Inc.
- Snaedis Kristmundsdottir
- deCODE genetics/Amgen, Inc.
- Olafur A. Stefansson
- deCODE genetics/Amgen, Inc.
- Solbritt Rantapää-Dahlqvist
- Department of Public Health and Clinical Medicine, Rheumatology, Umea University
- Ida Elken Sonderby
- Department of Medical Genetics, Oslo University Hospital and University of Oslo
- Maria Didriksen
- Department of Clinical Immunology, Copenhagen University Hospital
- Pernilla Stridh
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet
- Jan Haavik
- Department of Biomedicine, University of Bergen
- Laufey Tryggvadottir
- Icelandic Cancer Registry, Icelandic Cancer Society
- Oleksandr Frei
- NORMENT Centre, University of Oslo
- G. Bragi Walters
- deCODE genetics/Amgen, Inc.
- Ingrid Kockum
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet
- Henrik Hjalgrim
- Department of Clinical Medicine, Faculty of Health, University of Copenhagen
- Thorunn A. Olafsdottir
- deCODE genetics/Amgen, Inc.
- Geir Selbaek
- Norwegian National Centre of Ageing and Health, Vestfold Hospital Trust
- Mette Nyegaard
- Deptartment of Health Science and Technology, Aalborg University
- Christian Erikstrup
- Department of Clinical Immunology, Aarhus University Hospital
- Thorsten Brodersen
- Department of Clinical Immunology, Zealand University Hospital
- Saedis Saevarsdottir
- deCODE genetics/Amgen, Inc.
- Tomas Olsson
- Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Karolinska University Hospital, Karolinska Institutet
- Kaspar Rene Nielsen
- Department of Clinical Immunology, Aalborg University Hospital
- Asgeir Haraldsson
- Faculty of Medicine, School of Health Sciences, University of Iceland
- Mie Topholm Bruun
- Department of Clinical Immunology, Odense University Hospital
- Thomas Folkmann Hansen
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- DBDS Genomic Consortium
- Thora Steingrimsdottir
- Faculty of Medicine, School of Health Sciences, University of Iceland
- Rikke Louise Jacobsen
- Department of Clinical Immunology, Copenhagen University Hospital
- Rolv T. Lie
- Department of Global Public Health and Primary Care, University of Bergen
- Srdjan Djurovic
- Department of Medical Genetics, Oslo University Hospital and University of Oslo
- Lars Alfredsson
- Institute of Environmental Medicine, Karolinska Institutet
- Aitzkoa Lopez de Lapuente Portilla
- Hematology and Transfusion Medicine, Department of Laboratory Medicine
- Soren Brunak
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Pall Melsted
- deCODE genetics/Amgen, Inc.
- Bjarni V. Halldorsson
- deCODE genetics/Amgen, Inc.
- Jona Saemundsdottir
- deCODE genetics/Amgen, Inc.
- Olafur Th. Magnusson
- deCODE genetics/Amgen, Inc.
- Leonid Padyukov
- Department of Medicine, Solna, Karolinska Institutet
- Karina Banasik
- Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen
- Thorunn Rafnar
- deCODE genetics/Amgen, Inc.
- Johan Askling
- Department of Medicine, Solna, Karolinska Institutet
- Lars Klareskog
- Department of Medicine, Solna, Karolinska Institutet
- Ole Birger Pedersen
- Department of Clinical Medicine, Faculty of Health, University of Copenhagen
- Gisli Masson
- deCODE genetics/Amgen, Inc.
- Alexandra Havdahl
- Department of Mental Disorders, Norwegian Institute of Public Health
- Bjorn Nilsson
- Hematology and Transfusion Medicine, Department of Laboratory Medicine
- Ole A. Andreassen
- NORMENT Centre, University of Oslo
- Mark Daly
- Institute for Molecular Medicine, Finland, University of Helsinki
- Sisse Rye Ostrowski
- Department of Clinical Immunology, Copenhagen University Hospital
- Ingileif Jonsdottir
- deCODE genetics/Amgen, Inc.
- Hreinn Stefansson
- deCODE genetics/Amgen, Inc.
- Hilma Holm
- deCODE genetics/Amgen, Inc.
- Agnar Helgason
- deCODE genetics/Amgen, Inc.
- Unnur Thorsteinsdottir
- deCODE genetics/Amgen, Inc.
- Kari Stefansson
- deCODE genetics/Amgen, Inc.
- Daniel F. Gudbjartsson
- deCODE genetics/Amgen, Inc.
- DOI
- https://doi.org/10.1038/s41467-023-38951-2
- Journal volume & issue
-
Vol. 14,
no. 1
pp. 1 – 15
Abstract
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.
