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

Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Oddsson, A., Sulem, P., Sveinbjornsson, G., Arnadottir, G. A., Steinthorsdottir, V., Halldorsson, G. H., Atlason, B. A., Oskarsson, G. R., Helgason, H., Nielsen, H. S., Westergaard, D., Karjalainen, J. M., Katrinardottir, H., Fridriksdottir, R., Jensson, B. O., Tragante, V., Ferkingstad, E., Jonsson, H., Gudjonsson, S. A., Beyter, D., Moore, K. H. S., Thordardottir, H. B., Kristmundsdottir, S., Stefansson, O. A., Rantapää-Dahlqvist, S., Sonderby, I. E., Didriksen, M., Stridh, P., Haavik, J., Tryggvadottir, L., Frei, O., Walters, G. B., Kockum, I., Hjalgrim, H., Olafsdottir, T. A., Selbaek, G., Nyegaard, M., Erikstrup, C., Brodersen, T., Saevarsdottir, S., Olsson, T., Nielsen, K. R., Haraldsson, A., Bruun, M. T., Hansen, T. F., DBDS Genomic Consortium, Brunak, S., Nielsen, K. R., Brun, M. T., Stefánsson, H., Þorsteinsdóttir, U., Steingrimsdottir, T., Jacobsen, R. L., Lie, R. T., Djurovic, S., Alfredsson, L., Lopez De Lapuente Portilla, A., Brunak, S., Melsted, P., Halldorsson, B. V., Saemundsdottir, J., Magnusson, O. T., Padyukov, L., Banasik, K., Rafnar, T., Askling, J., Klareskog, L., Pedersen, O. B., Masson, G., Havdahl, A., Nilsson, B., Andreassen, O. A., Daly, M., Ostrowski, S. R., Jonsdottir, I., Stefansson, H., Holm, H., Helgason, A., Thorsteinsdottir, U., Stefansson, K., & Gudbjartsson, D. F. Nature Communications, 14(1):3453, June, 2023.

Paper doi abstract bibtex

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.

@article{oddssonDeficitHomozygosity1522023,
title = {Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality},
volume = {14},
issn = {2041-1723},
url = {https://www.nature.com/articles/s41467-023-38951-2},
doi = {10.1038/s41467-023-38951-2},
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.},
language = {en},
number = {1},
urldate = {2025-03-26},
journal = {Nature Communications},
author = {Oddsson, Asmundur and Sulem, Patrick and Sveinbjornsson, Gardar and Arnadottir, Gudny A. and Steinthorsdottir, Valgerdur and Halldorsson, Gisli H. and Atlason, Bjarni A. and Oskarsson, Gudjon R. and Helgason, Hannes and Nielsen, Henriette Svarre and Westergaard, David and Karjalainen, Juha M. and Katrinardottir, Hildigunnur and Fridriksdottir, Run and Jensson, Brynjar O. and Tragante, Vinicius and Ferkingstad, Egil and Jonsson, Hakon and Gudjonsson, Sigurjon A. and Beyter, Doruk and Moore, Kristjan H. S. and Thordardottir, Helga B. and Kristmundsdottir, Snaedis and Stefansson, Olafur A. and Rantapää-Dahlqvist, Solbritt and Sonderby, Ida Elken and Didriksen, Maria and Stridh, Pernilla and Haavik, Jan and Tryggvadottir, Laufey and Frei, Oleksandr and Walters, G. Bragi and Kockum, Ingrid and Hjalgrim, Henrik and Olafsdottir, Thorunn A. and Selbaek, Geir and Nyegaard, Mette and Erikstrup, Christian and Brodersen, Thorsten and Saevarsdottir, Saedis and Olsson, Tomas and Nielsen, Kaspar Rene and Haraldsson, Asgeir and Bruun, Mie Topholm and Hansen, Thomas Folkmann and {DBDS Genomic Consortium} and Brunak, Søren and Nielsen, Kasper Rene and Brun, Mie Topholm and Stefánsson, Hreinn and Þorsteinsdóttir, Unnur and Steingrimsdottir, Thora and Jacobsen, Rikke Louise and Lie, Rolv T. and Djurovic, Srdjan and Alfredsson, Lars and Lopez De Lapuente Portilla, Aitzkoa and Brunak, Soren and Melsted, Pall and Halldorsson, Bjarni V. and Saemundsdottir, Jona and Magnusson, Olafur Th. and Padyukov, Leonid and Banasik, Karina and Rafnar, Thorunn and Askling, Johan and Klareskog, Lars and Pedersen, Ole Birger and Masson, Gisli and Havdahl, Alexandra and Nilsson, Bjorn and Andreassen, Ole A. and Daly, Mark and Ostrowski, Sisse Rye and Jonsdottir, Ingileif and Stefansson, Hreinn and Holm, Hilma and Helgason, Agnar and Thorsteinsdottir, Unnur and Stefansson, Kari and Gudbjartsson, Daniel F.},
month = jun,
year = {2023},
pages = {3453},
}

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