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

doi:10.1038/s41467-023-38951-2

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 BeyterKristjan 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

^*Corresponding author for this work

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Article number	3453
Journal	Nature Communications
Volume	14
Issue number	1
Number of pages	15
ISSN	2041-1723
DOIs	https://doi.org/10.1038/s41467-023-38951-2
Publication status	Published - 10 Jun 2023

Bibliographical note

A correction has been published: https://doi.org/10.1038/s41467-023-39492-4

The original version of the Article omitted to include a statement to indicate Kari Stefansson and Daniel F. Gudbjartsson have jointly supervised the work. This has been corrected in both the PDF and HTML versions of the Article.

© 2023. The Author(s).

Keywords

Animals
Genes, Recessive
Genotype
Homozygote
Humans
Mice
Proteins/genetics

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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., ... Gudbjartsson, D. F. (2023). Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality. Nature Communications, 14(1), Article 3453. https://doi.org/10.1038/s41467-023-38951-2

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title = "Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality",

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.",

keywords = "Animals, Genes, Recessive, Genotype, Homozygote, Humans, Mice, Proteins/genetics",

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

note = "A correction has been published: https://doi.org/10.1038/s41467-023-39492-4 The original version of the Article omitted to include a statement to indicate Kari Stefansson and Daniel F. Gudbjartsson have jointly supervised the work. This has been corrected in both the PDF and HTML versions of the Article. {\textcopyright} 2023. The Author(s).",

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doi = "10.1038/s41467-023-38951-2",

language = "English",

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Oddsson, A, Sulem, P, Sveinbjornsson, G, Arnadottir, GA, Steinthorsdottir, V, Halldorsson, GH, Atlason, BA, Oskarsson, GR, Helgason, H, Nielsen, HS, Westergaard, D, Karjalainen, JM, Katrinardottir, H, Fridriksdottir, R, Jensson, BO, Tragante, V, Ferkingstad, E, Jonsson, H, Gudjonsson, SA, Beyter, D, Moore, KHS, Thordardottir, HB, Kristmundsdottir, S, Stefansson, OA, Rantapää-Dahlqvist, S, Sonderby, IE, Didriksen, M, Stridh, P, Haavik, J, Tryggvadottir, L, Frei, O, Walters, GB, Kockum, I, Hjalgrim, H, Olafsdottir, TA, Selbaek, G, Nyegaard, M, Erikstrup, C, Brodersen, T, Saevarsdottir, S, Olsson, T, Nielsen, KR, Haraldsson, A, Bruun, MT, Hansen, TF, DBDS Genomic Consortium, Steingrimsdottir, T, Jacobsen, RL, Lie, RT, Djurovic, S, Alfredsson, L, Lopez de Lapuente Portilla, A, Brunak, S, Melsted, P, Halldorsson, BV, Saemundsdottir, J, Magnusson, OT, Padyukov, L, Banasik, K, Rafnar, T, Askling, J, Klareskog, L, Pedersen, OB, Masson, G, Havdahl, A, Nilsson, B, Andreassen, OA, Daly, M, Ostrowski, SR, Jonsdottir, I, Stefansson, H, Holm, H, Helgason, A, Thorsteinsdottir, U, Stefansson, K & Gudbjartsson, DF 2023, 'Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality', Nature Communications, vol. 14, no. 1, 3453. https://doi.org/10.1038/s41467-023-38951-2

TY - JOUR

T1 - Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality

AU - Oddsson, Asmundur

AU - Sulem, Patrick

AU - Sveinbjornsson, Gardar

AU - Arnadottir, Gudny A

AU - Steinthorsdottir, Valgerdur

AU - Halldorsson, Gisli H

AU - Atlason, Bjarni A

AU - Oskarsson, Gudjon R

AU - Helgason, Hannes

AU - Nielsen, Henriette Svarre

AU - Westergaard, David

AU - Karjalainen, Juha M

AU - Katrinardottir, Hildigunnur

AU - Fridriksdottir, Run

AU - Jensson, Brynjar O

AU - Tragante, Vinicius

AU - Ferkingstad, Egil

AU - Jonsson, Hakon

AU - Gudjonsson, Sigurjon A

AU - Beyter, Doruk

AU - Moore, Kristjan H S

AU - Thordardottir, Helga B

AU - Kristmundsdottir, Snaedis

AU - Stefansson, Olafur A

AU - Rantapää-Dahlqvist, Solbritt

AU - Sonderby, Ida Elken

AU - Didriksen, Maria

AU - Stridh, Pernilla

AU - Haavik, Jan

AU - Tryggvadottir, Laufey

AU - Frei, Oleksandr

AU - Walters, G Bragi

AU - Kockum, Ingrid

AU - Hjalgrim, Henrik

AU - Olafsdottir, Thorunn A

AU - Selbaek, Geir

AU - Nyegaard, Mette

AU - Erikstrup, Christian

AU - Brodersen, Thorsten

AU - Saevarsdottir, Saedis

AU - Olsson, Tomas

AU - Nielsen, Kaspar Rene

AU - Haraldsson, Asgeir

AU - Bruun, Mie Topholm

AU - Hansen, Thomas Folkmann

AU - DBDS Genomic Consortium

AU - Steingrimsdottir, Thora

AU - Jacobsen, Rikke Louise

AU - Lie, Rolv T

AU - Djurovic, Srdjan

AU - Alfredsson, Lars

AU - Lopez de Lapuente Portilla, Aitzkoa

AU - Brunak, Soren

AU - Melsted, Pall

AU - Halldorsson, Bjarni V

AU - Saemundsdottir, Jona

AU - Magnusson, Olafur Th

AU - Padyukov, Leonid

AU - Banasik, Karina

AU - Rafnar, Thorunn

AU - Askling, Johan

AU - Klareskog, Lars

AU - Pedersen, Ole Birger

AU - Masson, Gisli

AU - Havdahl, Alexandra

AU - Nilsson, Bjorn

AU - Andreassen, Ole A

AU - Daly, Mark

AU - Ostrowski, Sisse Rye

AU - Jonsdottir, Ingileif

AU - Stefansson, Hreinn

AU - Holm, Hilma

AU - Helgason, Agnar

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Gudbjartsson, Daniel F

N1 - A correction has been published: https://doi.org/10.1038/s41467-023-39492-4 The original version of the Article omitted to include a statement to indicate Kari Stefansson and Daniel F. Gudbjartsson have jointly supervised the work. This has been corrected in both the PDF and HTML versions of the Article. © 2023. The Author(s).

PY - 2023/6/10

Y1 - 2023/6/10

N2 - 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.

AB - 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.

KW - Animals

KW - Genes, Recessive

KW - Genotype

KW - Homozygote

KW - Humans

KW - Mice

KW - Proteins/genetics

UR - http://www.scopus.com/inward/record.url?scp=85161942886&partnerID=8YFLogxK

U2 - 10.1038/s41467-023-38951-2

DO - 10.1038/s41467-023-38951-2

M3 - Journal article

C2 - 37301908

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 3453

ER -

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

Abstract

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Keywords

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