Research led by the University of Iceland and deCODE genetics has discovered a genetic variant that appears to significantly increase a woman’s risk of early menopause. The single nucleotide variant, known as rs117316434(A), results in a shortened protein being translated from the CCDC201 gene, which is highly expressed in egg cells.
The study, published in Nature Genetics, showed women with two copies of the variant have menopause approximately nine years earlier than average.
“There is a broad variation in the age of menopause, and early menopause impacts health, quality of life, and fertility potential,” the authors wrote. “It is estimated that natural fertility ends on average 10 years before menopause. At the extreme end of the age of menopause distribution is primary ovarian insufficiency with cessation of menses before the age of 40 years, which occurs in 1–4% of women.”
With women increasingly seeking to have children later in life, early menopause and primary ovarian insufficiency are important causes of infertility. This study set out to find rare genetic variants that may have a large impact on a woman’s chance of experiencing early menopause by analyzing genetic data from 174,329 postmenopausal women from Iceland, Denmark, and the U.K. from various deCODE databases, the Danish Blood Donor Study, and the UK Biobank.
The study uncovered the CCDC201 rs117316434(A) variant, which was linked to extremely early menopause when a copy was inherited from both parents. The researchers estimated that this genotype is found in around 1 in 10,000 women of Northern European ancestry and that more than half of them experience primary ovarian insufficiency.
Not much is known about the CCDC201 gene, and it was only discovered to be protein coding in 2022. However, the protein is known to be most strongly expressed in ovarian, breast, and placenta tissue, although it is also found in the testis. The sequence of the gene is quite well conserved across different species and the mouse version of the CCDC201 gene “has been identified as a target of the oocyte-specific transcription factor FIGLA, which is known to control early folliculogenesis without affecting male germ cell differentiation.”
The authors suggest that testing women for this genetic variant could help to better plan when to have children. “This would involve referring homozygotes to a fertility specialist to plan their reproductive life and treat symptoms of early menopause, as is done for other genetic causes of primary ovarian insufficiency.”
