Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency
Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analys...
Published in: | Nature Genetics |
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2024
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Online Access: | https://vbn.aau.dk/da/publications/0a7ea5ad-5690-4e90-99e0-184f9908283e https://doi.org/10.1038/s41588-024-01885-6 |
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ftalborgunivpubl:oai:pure.atira.dk:publications/0a7ea5ad-5690-4e90-99e0-184f9908283e 2024-09-15T18:14:05+00:00 Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency Oddsson, Asmundur Steinthorsdottir, Valgerdur Oskarsson, Gudjon R Styrkarsdottir, Unnur Moore, Kristjan H S Isberg, Salvor Halldorsson, Gisli H Sveinbjornsson, Gardar Westergaard, David Nielsen, Henriette Svarre Fridriksdottir, Run Jensson, Brynjar O Arnadottir, Gudny A Jonsson, Hakon Sturluson, Arni Snaebjarnarson, Audunn S Andreassen, Ole A Walters, G Bragi Nyegaard, Mette Erikstrup, Christian Steingrimsdottir, Thora Lie, Rolv T Melsted, Pall Jonsdottir, Ingileif Halldorsson, Bjarni V Thorleifsson, Gudmar Saemundsdottir, Jona Magnusson, Olafur Th Banasik, Karina Sorensen, Erik Masson, Gisli Pedersen, Ole Birger Tryggvadottir, Laufey Haavik, Jan Ostrowski, Sisse Rye Stefansson, Hreinn Holm, Hilma Rafnar, Thorunn Gudbjartsson, Daniel F Sulem, Patrick Stefansson, Kari 2024-08-27 https://vbn.aau.dk/da/publications/0a7ea5ad-5690-4e90-99e0-184f9908283e https://doi.org/10.1038/s41588-024-01885-6 eng eng https://vbn.aau.dk/da/publications/0a7ea5ad-5690-4e90-99e0-184f9908283e info:eu-repo/semantics/openAccess Oddsson , A , Steinthorsdottir , V , Oskarsson , G R , Styrkarsdottir , U , Moore , K H S , Isberg , S , Halldorsson , G H , Sveinbjornsson , G , Westergaard , D , Nielsen , H S , Fridriksdottir , R , Jensson , B O , Arnadottir , G A , Jonsson , H , Sturluson , A , Snaebjarnarson , A S , Andreassen , O A , Walters , G B , Nyegaard , M , Erikstrup , C , Steingrimsdottir , T , Lie , R T , Melsted , P , Jonsdottir , I , Halldorsson , B V , Thorleifsson , G , Saemundsdottir , J , Magnusson , O T , DBDS Genomic Consortium , Banasik , K , Sorensen , E , Masson , G , Pedersen , O B , Tryggvadottir , L , Haavik , J , Ostrowski , S R , Stefansson , H , Holm , H , Rafnar , T , Gudbjartsson , D F , Sulem , P & Stefansson , K 2024 , ' Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency ' , Nature Genetics . https://doi.org/10.1038/s41588-024-01885-6 article 2024 ftalborgunivpubl https://doi.org/10.1038/s41588-024-01885-6 2024-09-05T14:36:16Z Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10-15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10-5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. Article in Journal/Newspaper Iceland Aalborg University's Research Portal Nature Genetics 56 9 1804 1810 |
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Aalborg University's Research Portal |
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ftalborgunivpubl |
language |
English |
description |
Age at menopause (AOM) has a substantial impact on fertility and disease risk. While many loci with variants that associate with AOM have been identified through genome-wide association studies (GWAS) under an additive model, other genetic models are rarely considered1. Here through GWAS meta-analysis under the recessive model of 174,329 postmenopausal women from Iceland, Denmark, the United Kingdom (UK; UK Biobank) and Norway, we study low-frequency variants with a large effect on AOM. We discovered that women homozygous for the stop-gain variant rs117316434 (A) in CCDC201 (p.(Arg162Ter), minor allele frequency ~1%) reached menopause 9 years earlier than other women (P = 1.3 × 10-15). The genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them. Consequently, homozygotes have fewer children, and the age at last childbirth is 5 years earlier (P = 3.8 × 10-5). The CCDC201 gene was only found in humans in 2022 and is highly expressed in oocytes. Homozygosity for CCDC201 loss-of-function has a substantial impact on female reproductive health, and homozygotes would benefit from reproductive counseling and treatment for symptoms of early menopause. |
format |
Article in Journal/Newspaper |
author |
Oddsson, Asmundur Steinthorsdottir, Valgerdur Oskarsson, Gudjon R Styrkarsdottir, Unnur Moore, Kristjan H S Isberg, Salvor Halldorsson, Gisli H Sveinbjornsson, Gardar Westergaard, David Nielsen, Henriette Svarre Fridriksdottir, Run Jensson, Brynjar O Arnadottir, Gudny A Jonsson, Hakon Sturluson, Arni Snaebjarnarson, Audunn S Andreassen, Ole A Walters, G Bragi Nyegaard, Mette Erikstrup, Christian Steingrimsdottir, Thora Lie, Rolv T Melsted, Pall Jonsdottir, Ingileif Halldorsson, Bjarni V Thorleifsson, Gudmar Saemundsdottir, Jona Magnusson, Olafur Th Banasik, Karina Sorensen, Erik Masson, Gisli Pedersen, Ole Birger Tryggvadottir, Laufey Haavik, Jan Ostrowski, Sisse Rye Stefansson, Hreinn Holm, Hilma Rafnar, Thorunn Gudbjartsson, Daniel F Sulem, Patrick Stefansson, Kari |
spellingShingle |
Oddsson, Asmundur Steinthorsdottir, Valgerdur Oskarsson, Gudjon R Styrkarsdottir, Unnur Moore, Kristjan H S Isberg, Salvor Halldorsson, Gisli H Sveinbjornsson, Gardar Westergaard, David Nielsen, Henriette Svarre Fridriksdottir, Run Jensson, Brynjar O Arnadottir, Gudny A Jonsson, Hakon Sturluson, Arni Snaebjarnarson, Audunn S Andreassen, Ole A Walters, G Bragi Nyegaard, Mette Erikstrup, Christian Steingrimsdottir, Thora Lie, Rolv T Melsted, Pall Jonsdottir, Ingileif Halldorsson, Bjarni V Thorleifsson, Gudmar Saemundsdottir, Jona Magnusson, Olafur Th Banasik, Karina Sorensen, Erik Masson, Gisli Pedersen, Ole Birger Tryggvadottir, Laufey Haavik, Jan Ostrowski, Sisse Rye Stefansson, Hreinn Holm, Hilma Rafnar, Thorunn Gudbjartsson, Daniel F Sulem, Patrick Stefansson, Kari Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
author_facet |
Oddsson, Asmundur Steinthorsdottir, Valgerdur Oskarsson, Gudjon R Styrkarsdottir, Unnur Moore, Kristjan H S Isberg, Salvor Halldorsson, Gisli H Sveinbjornsson, Gardar Westergaard, David Nielsen, Henriette Svarre Fridriksdottir, Run Jensson, Brynjar O Arnadottir, Gudny A Jonsson, Hakon Sturluson, Arni Snaebjarnarson, Audunn S Andreassen, Ole A Walters, G Bragi Nyegaard, Mette Erikstrup, Christian Steingrimsdottir, Thora Lie, Rolv T Melsted, Pall Jonsdottir, Ingileif Halldorsson, Bjarni V Thorleifsson, Gudmar Saemundsdottir, Jona Magnusson, Olafur Th Banasik, Karina Sorensen, Erik Masson, Gisli Pedersen, Ole Birger Tryggvadottir, Laufey Haavik, Jan Ostrowski, Sisse Rye Stefansson, Hreinn Holm, Hilma Rafnar, Thorunn Gudbjartsson, Daniel F Sulem, Patrick Stefansson, Kari |
author_sort |
Oddsson, Asmundur |
title |
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
title_short |
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
title_full |
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
title_fullStr |
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
title_full_unstemmed |
Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
title_sort |
homozygosity for a stop-gain variant in ccdc201 causes primary ovarian insufficiency |
publishDate |
2024 |
url |
https://vbn.aau.dk/da/publications/0a7ea5ad-5690-4e90-99e0-184f9908283e https://doi.org/10.1038/s41588-024-01885-6 |
genre |
Iceland |
genre_facet |
Iceland |
op_source |
Oddsson , A , Steinthorsdottir , V , Oskarsson , G R , Styrkarsdottir , U , Moore , K H S , Isberg , S , Halldorsson , G H , Sveinbjornsson , G , Westergaard , D , Nielsen , H S , Fridriksdottir , R , Jensson , B O , Arnadottir , G A , Jonsson , H , Sturluson , A , Snaebjarnarson , A S , Andreassen , O A , Walters , G B , Nyegaard , M , Erikstrup , C , Steingrimsdottir , T , Lie , R T , Melsted , P , Jonsdottir , I , Halldorsson , B V , Thorleifsson , G , Saemundsdottir , J , Magnusson , O T , DBDS Genomic Consortium , Banasik , K , Sorensen , E , Masson , G , Pedersen , O B , Tryggvadottir , L , Haavik , J , Ostrowski , S R , Stefansson , H , Holm , H , Rafnar , T , Gudbjartsson , D F , Sulem , P & Stefansson , K 2024 , ' Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency ' , Nature Genetics . https://doi.org/10.1038/s41588-024-01885-6 |
op_relation |
https://vbn.aau.dk/da/publications/0a7ea5ad-5690-4e90-99e0-184f9908283e |
op_rights |
info:eu-repo/semantics/openAccess |
op_doi |
https://doi.org/10.1038/s41588-024-01885-6 |
container_title |
Nature Genetics |
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56 |
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9 |
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1804 |
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1810 |
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1810451869119545344 |