Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency

Asmundur Oddsson; Valgerdur Steinthorsdottir; Gudjon R. Oskarsson; Unnur Styrkarsdottir; Kristjan H.S. Moore; Salvor Isberg; Gisli H. Halldorsson; Gardar Sveinbjornsson; David Westergaard; Henriette Svarre Nielsen; Run Fridriksdottir; Brynjar O. Jensson; Gudny A. Arnadottir; Hakon Jonsson; Arni Sturluson; Audunn S. Snaebjarnarson; Ole A. Andreassen; G. Bragi Walters; Mette Nyegaard; Christian Erikstrup; Thora Steingrimsdottir; Rolv T. Lie; Pall Melsted; Ingileif Jonsdottir; Bjarni V. Halldorsson; Gudmar Thorleifsson; Jona Saemundsdottir; Olafur Th Magnusson; Karina Banasik; Erik Sorensen; Gisli Masson; Ole Birger Pedersen; Laufey Tryggvadottir; Jan Haavik; Sisse Rye Ostrowski; Hreinn Stefansson; Hilma Holm; Thorunn Rafnar; Daniel F. Gudbjartsson; Patrick Sulem; Kari Stefansson; DBDS Genomic Consortium

doi:10.1038/s41588-024-01885-6

Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency

Asmundur Oddsson, Valgerdur Steinthorsdottir, Gudjon R. Oskarsson, Unnur Styrkarsdottir, Kristjan H.S. Moore, Salvor Isberg, Gisli H. Halldorsson, Gardar Sveinbjornsson, David Westergaard, Henriette Svarre Nielsen, Run Fridriksdottir, Brynjar O. Jensson, Gudny A. Arnadottir, Hakon Jonsson, Arni Sturluson, Audunn S. Snaebjarnarson, Ole A. Andreassen, G. Bragi Walters, Mette Nyegaard, Christian ErikstrupThora Steingrimsdottir, Rolv T. Lie, Pall Melsted, Ingileif Jonsdottir, Bjarni V. Halldorsson, Gudmar Thorleifsson, Jona Saemundsdottir, Olafur Th Magnusson, Karina Banasik, Erik Sorensen, Gisli Masson, Ole Birger Pedersen, Laufey Tryggvadottir, Jan Haavik, Sisse Rye Ostrowski, Hreinn Stefansson, Hilma Holm, Thorunn Rafnar, Daniel F. Gudbjartsson, Patrick Sulem^*, Kari Stefansson, DBDS Genomic Consortium

^*Corresponding author for this work

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Abstract

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.

Original language	English
Journal	Nature Genetics
Volume	56
Issue number	9
Pages (from-to)	1804–1810
Number of pages	7
ISSN	1061-4036
DOIs	https://doi.org/10.1038/s41588-024-01885-6
Publication status	Published - 2024

Bibliographical note

Publisher Copyright:
© The Author(s) 2024.

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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., ... DBDS Genomic Consortium (2024). Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency. Nature Genetics, 56(9), 1804–1810. https://doi.org/10.1038/s41588-024-01885-6

Oddsson, A, Steinthorsdottir, V, Oskarsson, GR, Styrkarsdottir, U, Moore, KHS, Isberg, S, Halldorsson, GH, Sveinbjornsson, G, Westergaard, D, Nielsen, HS, Fridriksdottir, R, Jensson, BO, Arnadottir, GA, Jonsson, H, Sturluson, A, Snaebjarnarson, AS, Andreassen, OA, Walters, GB, Nyegaard, M, Erikstrup, C, Steingrimsdottir, T, Lie, RT, Melsted, P, Jonsdottir, I, Halldorsson, BV, Thorleifsson, G, Saemundsdottir, J, Magnusson, OT, Banasik, K, Sorensen, E, Masson, G, Pedersen, OB, Tryggvadottir, L, Haavik, J, Ostrowski, SR, Stefansson, H, Holm, H, Rafnar, T, Gudbjartsson, DF, Sulem, P, Stefansson, K & DBDS Genomic Consortium 2024, 'Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency', Nature Genetics, vol. 56, no. 9, pp. 1804–1810. https://doi.org/10.1038/s41588-024-01885-6

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title = "Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency",

abstract = "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.",

author = "Asmundur Oddsson and Valgerdur Steinthorsdottir and Oskarsson, {Gudjon R.} and Unnur Styrkarsdottir and Moore, {Kristjan H.S.} and Salvor Isberg and Halldorsson, {Gisli H.} and Gardar Sveinbjornsson and David Westergaard and Nielsen, {Henriette Svarre} and Run Fridriksdottir and Jensson, {Brynjar O.} and Arnadottir, {Gudny A.} and Hakon Jonsson and Arni Sturluson and Snaebjarnarson, {Audunn S.} and Andreassen, {Ole A.} and Walters, {G. Bragi} and Mette Nyegaard and Christian Erikstrup and Thora Steingrimsdottir and Lie, {Rolv T.} and Pall Melsted and Ingileif Jonsdottir and Halldorsson, {Bjarni V.} and Gudmar Thorleifsson and Jona Saemundsdottir and Magnusson, {Olafur Th} and Karina Banasik and Erik Sorensen and Gisli Masson and Pedersen, {Ole Birger} and Laufey Tryggvadottir and Jan Haavik and Ostrowski, {Sisse Rye} and Hreinn Stefansson and Hilma Holm and Thorunn Rafnar and Gudbjartsson, {Daniel F.} and Patrick Sulem and Kari Stefansson and {DBDS Genomic Consortium}",

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year = "2024",

doi = "10.1038/s41588-024-01885-6",

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volume = "56",

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TY - JOUR

T1 - Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency

AU - Oddsson, Asmundur

AU - Steinthorsdottir, Valgerdur

AU - Oskarsson, Gudjon R.

AU - Styrkarsdottir, Unnur

AU - Moore, Kristjan H.S.

AU - Isberg, Salvor

AU - Halldorsson, Gisli H.

AU - Sveinbjornsson, Gardar

AU - Westergaard, David

AU - Nielsen, Henriette Svarre

AU - Fridriksdottir, Run

AU - Jensson, Brynjar O.

AU - Arnadottir, Gudny A.

AU - Jonsson, Hakon

AU - Sturluson, Arni

AU - Snaebjarnarson, Audunn S.

AU - Andreassen, Ole A.

AU - Walters, G. Bragi

AU - Nyegaard, Mette

AU - Erikstrup, Christian

AU - Steingrimsdottir, Thora

AU - Lie, Rolv T.

AU - Melsted, Pall

AU - Jonsdottir, Ingileif

AU - Halldorsson, Bjarni V.

AU - Thorleifsson, Gudmar

AU - Saemundsdottir, Jona

AU - Magnusson, Olafur Th

AU - Banasik, Karina

AU - Sorensen, Erik

AU - Masson, Gisli

AU - Pedersen, Ole Birger

AU - Tryggvadottir, Laufey

AU - Haavik, Jan

AU - Ostrowski, Sisse Rye

AU - Stefansson, Hreinn

AU - Holm, Hilma

AU - Rafnar, Thorunn

AU - Gudbjartsson, Daniel F.

AU - Sulem, Patrick

AU - Stefansson, Kari

AU - DBDS Genomic Consortium

PY - 2024

Y1 - 2024

N2 - 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.

AB - 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.

U2 - 10.1038/s41588-024-01885-6

DO - 10.1038/s41588-024-01885-6

M3 - Letter

C2 - 39192094

AN - SCOPUS:85202455633

SN - 1061-4036

VL - 56

SP - 1804

EP - 1810

JO - Nature Genetics

JF - Nature Genetics

IS - 9

ER -