Newly discovered variants let women predict their fertility — and overall health.
A genetic study of 75,000 23andMe users may help young women predict their fertility timeline — and cast new light on women’s health more generally.
Celmatix, a diagnostics company in New York City, announced results today from the largest study to date of the genetics of early menopause. The condition, also called premature ovarian failure or primary ovarian insufficiency, affects 1 in 100 women under the age of 40. The study, which reports that variants in two genes increase a woman’s risk of developing this condition by 19 percent, was presented at the American Society for Reproductive Medicine’s annual congress in Denver this week.
Previous, smaller studies had hinted that these genetic variants play a role in early menopause, but they included too few women to generate conclusive results. The unprecedented scale of this study makes the new results more convincing — and potentially useful.
When a woman’s ovaries stop releasing eggs, and the production of estrogen and other hormones like progesterone declines, it becomes nearly impossible for her to conceive naturally. For most women, that happens between the ages of 45 and 55; when it happens to women in their 20s or 30s, it is considered early menopause. It’s not just a fertility problem: Early menopause can also increase a woman’s risk of cardiovascular disease, osteoporosis, and even breast and ovarian cancer.
That’s why testing for these variants could be useful for many women, not just those trying to get pregnant, says Celmatix founder and CEO Piraye Beim. “This [genetic] risk factor still matters for women who’ve made up their mind not to have children because it could be a canary in a coalmine for other things,” she says.
Several genetic panels are already on the market that can assess some risk factors for early menopause: Blueprint Genetics, GeneDx, the University of Chicago, and even Celmatix’s own Fertilome test all offer this service. However, these tests do not include the new variants because they were developed using what’s called a “candidate gene” approach, scanning for variants in genes that are already known to be involved with the underlying biology of that particular condition. That’s only useful if you know how a disorder works and what genes to look for.
It’s not just a fertility problem: Early menopause can also increase a woman’s risk of cardiovascular disease, osteoporosis, and even breast and ovarian cancer.
If the mechanisms of a disorder are poorly understood, as with early menopause, this approach may miss some important genes. Current versions of Fertilome have identified risk factors in 84 percent of Celmatix customers, but for 16 percent the condition was unexplained.
The company’s new study is a genome-wide association study, which means it starts at the other end — it looks in an unbiased way at a large population and finds commonalities in the genetic code of those who have a disorder in common. In this case, 3,219 of the 75,000 women in the 23andMe group reported that they’d had early menopause, allowing the research team to pinpoint associated variations in the genes BRSK1 and TMEM150B, which have not been included in existing panels.
BRSK1 normally acts as a checkpoint that stops a cell with damaged DNA from duplicating, and TMEM150B checks for cell quality control. Variants in these genes may cause a woman’s ovarian cells to die off more quickly, but the exact mechanisms underlying early menopause are still unknown.
“These types of studies are critically important to keep pushing us to further elucidate what the factors are that affect fertility and beyond,” says Stacey Missmer, a reproductive epidemiologist who teaches at both the Harvard School of Public Health and Michigan State University, and wasn’t involved in the Celmatix study. Women’s health has historically been understudied and the research into it under-funded, creating these kinds of knowledge gaps, she says.
Celmatix hopes to add these variants to its Fertilome test, but the company has not said when this will happen. The test, which must be ordered by a doctor, is currently not covered by insurance and costs $950.
A chance to beat the clock
Today, most women find out they’re going through early menopause only when it’s already too late — when they’re trying to get pregnant and cannot. At that point, not much can be done to restore fertility, although some treatments can address symptoms of early menopause.
Since most women assume they will be fertile well into their 30s, this discovery can be a painful surprise. “You are an individual and the shape of your [fertility timeline] may look different,” says Beim. And when it doesn’t work out for them, “women who base their life plans on these averages end up feeling very frustrated.”
Beim hopes that in the future a test that includes this new information will help more young women who plan to one day have children — especially those with a family history of early menopause — take fertility-preserving steps such as egg freezing while they still have time. It could also help any woman with the condition take preventive measures against the diseases associated with early menopause and those that become more common in women after menopause, such as stroke.
Since most women assume they will be fertile well into their 30s, this discovery can be a painful surprise.
Genome-wide association studies generally require generous funding and large populations, like the 75,000 women studied here, in order to reliably associate gene variants with disorders and diseases. Typically, a study this large would be challenging to execute with public money, says Missmer: “It’s extremely difficult to get funding to begin a rigorous, large-scale project that’s specifically focused on reproductive health” in academia, she says. “It feels like begging, borrowing, and stealing to do this work.”
Celmatix got its large pool of subjects by partnering with 23andMe, which provided the company with information from volunteers who had agreed to share their data for research. However, this wealth of data comes with a limitation: 23andMe’s customer base is dominated by people of European ancestry, and in this case the study was conducted only with people of that background. That means that any potential future test may not be as accurate for people of other ethnicities, although in previous smaller studies these variants were linked to age at menopause in African-American, Han Chinese, and Hispanic populations. Fertilome’s current version includes a disclaimer indicating that gene frequencies and associations may vary among ethnicities.
Beim says Celmatix plans to address this limitation with another, broader fertility study of about 4,500 women of diverse backgrounds, who are more representative of American demographics. “We don’t understand a lot about women’s health in general. We understand even less about the health of women of color, and that’s a real problem,” says Beim. That study is now in its final months.
