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 considered 1 . Here through GWAS meta-anal...

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Published in:	Nature genetics Vol. 56; no. 9; pp. 1804 - 1810
Main Authors:	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
Format:	Journal Article
Language:	English
Published:	New York Nature Publishing Group US 01-09-2024 Nature Publishing Group
Subjects:	45 45/23 45/43 631/136/2434/1706 631/208/205/2138 631/208/457 692/308/2056 692/699/2732/1577 Age Agriculture Animal Genetics and Genomics Biobanks Biomedical and Life Sciences Biomedicine Cancer Research Childbirth & labor Denmark Female Fertility Gametocytes Gene Frequency Gene Function Genetic analysis Genetic Predisposition to Disease Genome-wide association studies Genome-Wide Association Study Genomes Genotypes Health risks Homozygosity Homozygote Homozygotes Human Genetics Humans Iceland Infertility Letter Medical treatment Menopause Menopause - genetics Meta-analysis Middle Aged Oocytes Ovaries Polymorphism, Single Nucleotide Post-menopause Primary Ovarian Insufficiency - genetics Reproductive health United Kingdom Womens health Denmark United Kingdom Iceland United Kingdom > UK Norway
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Summary:	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 considered 1 . 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. Genome-wide analysis of age at menopause under a recessive model identifies a stop-gain variant in CCDC201 associated with primary ovarian insufficiency. This homozygous genotype is present in 1 in 10,000 women of northern European ancestry.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1061-4036 1546-1718 1546-1718
DOI:	10.1038/s41588-024-01885-6