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.

Genotypes causing pregnancy loss and perinatal mortality are depleted among living individuals and are therefore difficult to find. Here, using genetic data for 1.52 million individuals, the authors identify 25 genes with protein-altering variants exhibiting a strong deficit of homozygosity, suggesting they are essential for successful early development.

Details

Title
Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality
Author
Oddsson, Asmundur 1   VIAFID ORCID Logo  ; Sulem, Patrick 1   VIAFID ORCID Logo  ; Sveinbjornsson, Gardar 1   VIAFID ORCID Logo  ; Arnadottir, Gudny A. 2   VIAFID ORCID Logo  ; Steinthorsdottir, Valgerdur 1   VIAFID ORCID Logo  ; Halldorsson, Gisli H. 1   VIAFID ORCID Logo  ; Atlason, Bjarni A. 1   VIAFID ORCID Logo  ; Oskarsson, Gudjon R. 1   VIAFID ORCID Logo  ; Helgason, Hannes 1 ; Nielsen, Henriette Svarre 3   VIAFID ORCID Logo  ; Westergaard, David 4   VIAFID ORCID Logo  ; Karjalainen, Juha M. 5 ; Katrinardottir, Hildigunnur 1 ; Fridriksdottir, Run 1 ; Jensson, Brynjar O. 1   VIAFID ORCID Logo  ; Tragante, Vinicius 1   VIAFID ORCID Logo  ; Ferkingstad, Egil 1   VIAFID ORCID Logo  ; Jonsson, Hakon 1   VIAFID ORCID Logo  ; Gudjonsson, Sigurjon A. 1 ; Beyter, Doruk 1 ; Moore, Kristjan H. S. 6   VIAFID ORCID Logo  ; Thordardottir, Helga B. 2 ; Kristmundsdottir, Snaedis 1   VIAFID ORCID Logo  ; Stefansson, Olafur A. 1 ; Rantapää-Dahlqvist, Solbritt 7   VIAFID ORCID Logo  ; Sonderby, Ida Elken 8   VIAFID ORCID Logo  ; Didriksen, Maria 9   VIAFID ORCID Logo  ; Stridh, Pernilla 10   VIAFID ORCID Logo  ; Haavik, Jan 11   VIAFID ORCID Logo  ; Tryggvadottir, Laufey 12   VIAFID ORCID Logo  ; Frei, Oleksandr 13 ; Walters, G. Bragi 1   VIAFID ORCID Logo  ; Kockum, Ingrid 10   VIAFID ORCID Logo  ; Hjalgrim, Henrik 14 ; Olafsdottir, Thorunn A. 1   VIAFID ORCID Logo  ; Selbaek, Geir 15   VIAFID ORCID Logo  ; Nyegaard, Mette 16   VIAFID ORCID Logo  ; Erikstrup, Christian 17   VIAFID ORCID Logo  ; Brodersen, Thorsten 18   VIAFID ORCID Logo  ; Saevarsdottir, Saedis 2   VIAFID ORCID Logo  ; Olsson, Tomas 10 ; Nielsen, Kaspar Rene 19 ; Haraldsson, Asgeir 20 ; Bruun, Mie Topholm 21   VIAFID ORCID Logo  ; Hansen, Thomas Folkmann 22 ; Brunak, Søren 23 ; Nielsen, Kasper Rene 19 ; Brun, Mie Topholm 21 ; Stefánsson, Hreinn 1 ; Þorsteinsdóttir, Unnur 2 ; Steingrimsdottir, Thora 24 ; Jacobsen, Rikke Louise 9   VIAFID ORCID Logo  ; Lie, Rolv T. 25   VIAFID ORCID Logo  ; Djurovic, Srdjan 8   VIAFID ORCID Logo  ; Alfredsson, Lars 26   VIAFID ORCID Logo  ; Lopez de Lapuente Portilla, Aitzkoa 27 ; Brunak, Soren 23   VIAFID ORCID Logo  ; Melsted, Pall 28 ; Halldorsson, Bjarni V. 29   VIAFID ORCID Logo  ; Saemundsdottir, Jona 1 ; Magnusson, Olafur Th. 1 ; Padyukov, Leonid 30   VIAFID ORCID Logo  ; Banasik, Karina 23   VIAFID ORCID Logo  ; Rafnar, Thorunn 1   VIAFID ORCID Logo  ; Askling, Johan 30 ; Klareskog, Lars 30   VIAFID ORCID Logo  ; Pedersen, Ole Birger 31   VIAFID ORCID Logo  ; Masson, Gisli 1 ; Havdahl, Alexandra 32   VIAFID ORCID Logo  ; Nilsson, Bjorn 27   VIAFID ORCID Logo  ; Andreassen, Ole A. 33   VIAFID ORCID Logo  ; Daly, Mark 34 ; Ostrowski, Sisse Rye 35   VIAFID ORCID Logo  ; Jonsdottir, Ingileif 2   VIAFID ORCID Logo  ; Stefansson, Hreinn 1 ; Holm, Hilma 1   VIAFID ORCID Logo  ; Helgason, Agnar 6 ; Thorsteinsdottir, Unnur 2 ; Stefansson, Kari 2   VIAFID ORCID Logo  ; Gudbjartsson, Daniel F. 29   VIAFID ORCID Logo 

1  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889) 
2  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
3  Copenhagen University Hospital, Deptartment of Obstetrics and Gynecology, Hvidovre, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373); Faculty of Health, University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
4  Copenhagen University Hospital, Deptartment of Obstetrics and Gynecology, Hvidovre, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373); University of Copenhagen, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Methods and Analysis, Statistics Denmark, Copenhagen, Denmark (GRID:grid.437930.a) (ISNI:0000 0001 2248 6353) 
5  University of Helsinki, Institute for Molecular Medicine, Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071) 
6  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, Department of Anthropology, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
7  Umea University, Department of Public Health and Clinical Medicine, Rheumatology, Umea, Sweden (GRID:grid.12650.30) (ISNI:0000 0001 1034 3451) 
8  Oslo University Hospital and University of Oslo, Department of Medical Genetics, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, NORMENT Centre, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, KG Jebsen Centre for Neurodevelopmental disorders, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
9  Copenhagen University Hospital, Department of Clinical Immunology, Copenhagen, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373) 
10  Karolinska University Hospital, Karolinska Institutet, Neuroimmunology Unit, Department of Clinical Neuroscience, Center of Molecular Medicine, Stockholm, Sweden (GRID:grid.24381.3c) (ISNI:0000 0000 9241 5705) 
11  University of Bergen, Department of Biomedicine, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443); Haukeland University Hospital, Bergen Center of Brain Plasticity, Division of Psychiatry, Bergen, Norway (GRID:grid.412008.f) (ISNI:0000 0000 9753 1393) 
12  Icelandic Cancer Society, Icelandic Cancer Registry, Reykjavik, Iceland (GRID:grid.507118.a) (ISNI:0000 0001 0329 4954); University of Iceland, Faculty of Medicine, BMC, Laeknagardur, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
13  University of Oslo, NORMENT Centre, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Division of Mental Health and Addiction, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Centre for Bioinformatics, Department of Informatics, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
14  Faculty of Health, University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Danish Cancer Society Research Center, Copenhagen, Denmark (GRID:grid.417390.8) (ISNI:0000 0001 2175 6024); Statens Serum Institut, Department of Epidemiology Research, Copenhagen, Denmark (GRID:grid.6203.7) (ISNI:0000 0004 0417 4147) 
15  Vestfold Hospital Trust, Norwegian National Centre of Ageing and Health, Tonsberg, Norway (GRID:grid.417292.b) (ISNI:0000 0004 0627 3659); Oslo University Hospital, Department of Geriatric Medicine, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485); University of Oslo, Faculty of Medicine, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
16  Aalborg University, Deptartment of Health Science and Technology, Aalborg, Denmark (GRID:grid.5117.2) (ISNI:0000 0001 0742 471X) 
17  Aarhus University Hospital, Department of Clinical Immunology, Aarhus, Denmark (GRID:grid.154185.c) (ISNI:0000 0004 0512 597X); Aarhus University, Department of Clinical Medicine, Aarhus, Denmark (GRID:grid.7048.b) (ISNI:0000 0001 1956 2722) 
18  Zealand University Hospital, Department of Clinical Immunology, Koge, Denmark (GRID:grid.512923.e) (ISNI:0000 0004 7402 8188) 
19  Aalborg University Hospital, Department of Clinical Immunology, Aalborg, Denmark (GRID:grid.27530.33) (ISNI:0000 0004 0646 7349) 
20  University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021); Landspitali University Hospital, Children’s Hospital Iceland, Reykjavik, Iceland (GRID:grid.410540.4) (ISNI:0000 0000 9894 0842) 
21  Odense University Hospital, Department of Clinical Immunology, Odense, Denmark (GRID:grid.7143.1) (ISNI:0000 0004 0512 5013) 
22  University of Copenhagen, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Copenhagen University Hospital, Department of Neurology, Glostrup, Denmark (GRID:grid.411719.b) (ISNI:0000 0004 0630 0311) 
23  University of Copenhagen, Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
24  University of Iceland, Faculty of Medicine, School of Health Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
25  University of Bergen, Department of Global Public Health and Primary Care, Bergen, Norway (GRID:grid.7914.b) (ISNI:0000 0004 1936 7443); Norwegian Institute of Public Health, Centre for Fertility and Health, Oslo, Norway (GRID:grid.418193.6) (ISNI:0000 0001 1541 4204) 
26  Karolinska Institutet, Institute of Environmental Medicine, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
27  Department of Laboratory Medicine, Hematology and Transfusion Medicine, Lund, Sweden (GRID:grid.4514.4) (ISNI:0000 0001 0930 2361) 
28  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); University of Iceland, School of Engineering and Natural Sciences, Reykjavik, Iceland (GRID:grid.14013.37) (ISNI:0000 0004 0640 0021) 
29  deCODE genetics/Amgen, Inc., Reykjavik, Iceland (GRID:grid.421812.c) (ISNI:0000 0004 0618 6889); Reykjavik University, School of Science and Engineering, Reykjavik, Iceland (GRID:grid.9580.4) (ISNI:0000 0004 0643 5232) 
30  Karolinska Institutet, Department of Medicine, Solna, Stockholm, Sweden (GRID:grid.4714.6) (ISNI:0000 0004 1937 0626) 
31  Faculty of Health, University of Copenhagen, Department of Clinical Medicine, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X); Zealand University Hospital, Department of Clinical Immunology, Koge, Denmark (GRID:grid.512923.e) (ISNI:0000 0004 7402 8188) 
32  Norwegian Institute of Public Health, Department of Mental Disorders, Oslo, Norway (GRID:grid.418193.6) (ISNI:0000 0001 1541 4204); Lovisenberg Diaconal Hospital, Nic Waals Institute, Oslo, Norway (GRID:grid.416137.6) (ISNI:0000 0004 0627 3157); University of Oslo, PROMENTA Research Center, Department of Psychology, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921) 
33  University of Oslo, NORMENT Centre, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); University of Oslo, KG Jebsen Centre for Neurodevelopmental disorders, Oslo, Norway (GRID:grid.5510.1) (ISNI:0000 0004 1936 8921); Oslo University Hospital, Division of Mental Health and Addiction, Oslo, Norway (GRID:grid.55325.34) (ISNI:0000 0004 0389 8485) 
34  University of Helsinki, Institute for Molecular Medicine, Finland, Helsinki, Finland (GRID:grid.7737.4) (ISNI:0000 0004 0410 2071); Massachusetts General Hospital, Analytic and Translational Genetics Unit, Boston, USA (GRID:grid.32224.35) (ISNI:0000 0004 0386 9924); Broad Institute of MIT and Harvard, Cambridge, USA (GRID:grid.66859.34) (ISNI:0000 0004 0546 1623) 
35  Copenhagen University Hospital, Department of Clinical Immunology, Copenhagen, Denmark (GRID:grid.4973.9) (ISNI:0000 0004 0646 7373); University of Copenhagen, Deptartment of Clinical Medicine, Faculty of Health and Medical Sciences, Copenhagen, Denmark (GRID:grid.5254.6) (ISNI:0000 0001 0674 042X) 
Pages
3453
Publication year
2023
Publication date
2023
Publisher
Nature Publishing Group
e-ISSN
20411723
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41467-023-38951-2
ProQuest document ID
2825562457
Copyright
© The Author(s) 2023. corrected publication 2023. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.