| Title: | Homozygosity for a stop-gain variant in CCDC201 causes primary ovarian insufficiency |
| Journal: | Nature Genetics |
| Published: | 27 Aug 2024 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/39192094/ |
| DOI: | https://doi.org/10.1038/s41588-024-01885-6 |
Publication 13076
WARNING: the interactive features of this website use CSS3, which your browser does not support. To use the full features of this website, please update your browser.
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.</p>
41 Authors
- 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
1 Application
| Application ID | Title |
|---|---|
| 56270 | Evaluating and comparing sequence variant associations between the deCODE and UK Biobank datasets across a range of human traits |
Enabling scientific discoveries that improve human health