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; Thora Steingrimsdottir; Rikke Louise Jacobsen; Soren Brunak; Ole Birger Pedersen; Sisse Rye Ostrowski; DBDS Genomic Consortium

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, Thora Steingrimsdottir, Rikke Louise Jacobsen, Soren Brunak, Ole Birger Pedersen, Sisse Rye Ostrowski, DBDS Genomic Consortium

^*Corresponding author af dette arbejde

6 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	3453
Tidsskrift	Nature Communications
Vol/bind	14
Udgave nummer	1
ISSN	2041-1722
DOI	https://doi.org/10.1038/s41467-023-38951-2
Status	Udgivet - 10 jun. 2023

Adgang til dokumentet

10.1038/s41467-023-38951-2

Andre filer og links

Link to publication in Scopus

Citationsformater

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

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, Steingrimsdottir, T, Jacobsen, RL, Brunak, S, Pedersen, OB, Ostrowski, SR & DBDS Genomic Consortium 2023, 'Deficit of homozygosity among 1.52 million individuals and genetic causes of recessive lethality', Nature Communications, bind 14, nr. 1, 3453. https://doi.org/10.1038/s41467-023-38951-2

@article{10b8e86a04dd4cf9a415574be65fd88f,

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.",

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 Thora Steingrimsdottir and Jacobsen, {Rikke Louise} and Soren Brunak and Pedersen, {Ole Birger} and Ostrowski, {Sisse Rye} and {DBDS Genomic Consortium}",

note = "{\textcopyright} 2023. The Author(s).",

year = "2023",

month = jun,

day = "10",

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

language = "English",

volume = "14",

journal = "Nature Communications",

issn = "2041-1722",

publisher = "Nature Publishing Group",

number = "1",

}

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 - Steingrimsdottir, Thora

AU - Jacobsen, Rikke Louise

AU - Brunak, Soren

AU - Pedersen, Ole Birger

AU - Ostrowski, Sisse Rye

AU - DBDS Genomic Consortium

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.

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 - 2041-1722

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

Adgang til dokumentet

Andre filer og links

Fingeraftryk

Citationsformater