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. 2024 Sep;56(9):1804-1810.
doi: 10.1038/s41588-024-01885-6. Epub 2024 Aug 27.

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

Asmundur Oddsson  1 , Valgerdur Steinthorsdottir  1 , Gudjon R Oskarsson  1 , Unnur Styrkarsdottir  1 , Kristjan H S Moore  1   2 , Salvor Isberg  1 , Gisli H Halldorsson  1 , Gardar Sveinbjornsson  1 , David Westergaard  3   4   5 , Henriette Svarre Nielsen  5   6 , Run Fridriksdottir  1 , Brynjar O Jensson  1 , Gudny A Arnadottir  1 , Hakon Jonsson  1 , Arni Sturluson  1 , Audunn S Snaebjarnarson  1 , Ole A Andreassen  7   8   9 , G Bragi Walters  1 , Mette Nyegaard  10 , Christian Erikstrup  11   12 , Thora Steingrimsdottir  13 , Rolv T Lie  14   15 , Pall Melsted  1   16 , Ingileif Jonsdottir  1   13 , Bjarni V Halldorsson  1   17 , Gudmar Thorleifsson  1 , Jona Saemundsdottir  1 , Olafur Th Magnusson  1 ; DBDS Genomic Consortium; Karina Banasik  3 , Erik Sorensen  18 , Gisli Masson  1 , Ole Birger Pedersen  6   19 , Laufey Tryggvadottir  20   21 , Jan Haavik  22   23 , Sisse Rye Ostrowski  18   24 , Hreinn Stefansson  1 , Hilma Holm  1 , Thorunn Rafnar  1 , Daniel F Gudbjartsson  1   16 , Patrick Sulem  25 , Kari Stefansson  26   27
Collaborators, Affiliations

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

Asmundur Oddsson et al. Nat Genet. 2024 Sep.

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.

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Conflict of interest statement

Authors affiliated with deCODE genetics/Amgen declare competing interests as employees. The remaining authors declare no competing interests.

Figures

Fig. 1
Fig. 1. Regional association plot for the CCDC201 locus (7q12.3), flanking 550 kb on either side of the p.(Arg162Ter) variant, indicated as a diamond on the plot (chr7: 45863165G>A).
Under a recessive model, variant associations with AOM are plotted against their NCBI Build 38 positions at the CCDC201 locus, colored by the strength of correlation, r2, to p.(Arg162Ter). LD data are based on the UK Biobank, and white circles represent variants absent from the UK Biobank. Known genes are shown in the plot. P values are two-sided without Bonferroni correction calculated based on an inverse variance-weighted fixed-effects meta-analysis. NA, not available.
Fig. 2
Fig. 2. Distribution of age of menopause by population and genotype.
a–d, Age of menopause for p.(Arg162Ter) homozygotes (red), heterozygotes and noncarriers (blue) by population in the UK (a), ISL (b), DNK (c) and NOR (d). The dashed line indicates the mean age of menopause. ISL, Iceland; DNK, Denmark; NOR, Norway; UK, UK Biobank; Het, Heterozygotes.
Fig. 3
Fig. 3. Distribution of maternal age at childbirth and number of children by population and genotype.
a,b, Maternal age at childbirth for p.(Arg162Ter) homozygotes (red), heterozygotes and noncarriers (blue) by population in ISL (a) and the UK (b). The dashed line indicates the mean age at childbirth. c, Distribution of the percentage of mothers having children by age bins. Maternal age at childbirth for p.(Arg162Ter) homozygotes (red), heterozygotes and noncarriers (blue) by population in the UK and ISL. d–g, Number of children born to p.(Arg162Ter) homozygotes (red) and heterozygotes and noncarriers (blue) women by population in ISL (d), the UK (e), DNK (f) and NOR (g). The dashed line indicates the mean number of children.
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