Gene variant identified that can cause early menopause

Menopause occurs an average of nine years earlier in women with two copies of a variant of the CCDC201 gene.

Researchers from the University of Iceland and deCODE genetics, Reykjavík, Iceland, discovered that a variant in the CCDC201 gene significantly increases the risk of early menopause in women when two copies are inherited. On average, women with this genotype experience menopause nine years earlier than women who do not.

'There is a broad variation in the age of menopause, and early menopause impacts health, quality of life and fertility potential,' the study authors wrote in their paper published in Nature Genetics. 'It is estimated that natural fertility ends on average ten years before menopause. At the extreme end of the age of menopause distribution is primary ovarian insufficiency… which occurs in one to four percent of women.'

However, primary ovarian insufficiency, defined as experiencing menopause before the age of 40, was discovered in nearly half of women with two copies of the CCDC201 gene variant.

The researchers conducted a genome-wide association study using data from over 174,000 postmenopausal women from Iceland, Denmark and the UK. In particular, the researchers focused their search on homozygotes, people with two identical alleles of a particular gene.

The researchers discovered that when a copy of a particular variant of the CCDC201 gene was inherited from both parents, a complete loss of the gene's function occurred. This loss of function resulted in increasing a woman's risk of early menopause.

The researchers explained that 'the [homozygous] genotype is present in one in 10,000 northern European women and leads to primary ovarian insufficiency in close to half of them'.

Women with this homozygous genotype had fewer children and only rarely had children after the age of 30.

Prior studies have identified many gene variants that increase a woman's risk of early menopause when only one copy of the variant is present. However, it is unlikely that any previously identified genes are solely responsible for causing primary ovarian insufficiency (see BioNews 1197).

This study shows the impact of this rare homozygous genotype on reproductive health, highlighting the importance of considering different genetic models when studying diseases.

Early diagnosis of primary ovarian insufficiency would allow for informed reproductive choices and improved management of the symptoms associated with early menopause. Authors of this study advocate for the potential benefits of genetic counselling for people with this homozygous genotype, and suggest referring them '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.'