An illustration of polycystic ovarian syndrome, which causes enlargement of the ovaries
Scientific photo library / Alamy
We finally address the genetics of polycystic ovary syndrome (PCOS), which could open the door to new treatments.
PCOS, which is estimated to affect up to 1 in 5 women, disrupts the functioning of the ovaries, leading to at least two of three characteristics: irregular or no periods; high levels of male sex hormones, including testosterone; and a buildup of immature eggs that look like cysts in the ovaries. As a result, fertility problems are common with this disease.
Its exact cause is unknown, but PCOS has been linked to changes in the gut microbiome and hormonal imbalances before birth. This disease is also hereditary: studies estimate that around 70% of individual risk is due to genetics. But until now, researchers had identified only about 25 genetic variants — involved in the production of sex hormones, like estrogen and testosterone, and in ovarian function — that explain about 10 percent of a person’s risk.
To fill this knowledge gap, Shigang Zhao of Shandong University in Jinan, China, and colleagues analyzed the genomes of more than 440,000 women in China and Europe, 25,000 of whom had been diagnosed with PCOS, while the rest had not, in the largest genetic analysis of the disease to date.
The team identified 94 genetic variants that appear to influence PCOS risk, 73 of which had not been previously identified. One of the most interesting variants is found in the gene encoding the mitochondrial ribosomal protein S22, which helps mitochondria, the energy-generating parts of cells, function properly, Zhao says. While previous studies have linked PCOS to dysfunctional mitochondria, this is the first look at how genetics may be behind this phenomenon, he says.
Another newly identified variant affects a protein called sex hormone-binding globulin, which regulates sex hormone activity and is commonly found at low levels in people with PCOS.
Most of the remaining variants influence the functioning of the ovary’s granulosa cells — which produce estrogen and progesterone and help eggs develop — throughout the menstrual cycle. This supports the idea that genetics determine PCOS by changing sex hormone levels, Zhao says.
Overall, the team calculated that the 94 variants explained about 27 percent of the variation in PCOS risk among European participants and about 34 percent of the risk among Chinese populations.
“This study is important because it expands our understanding of the genetic component of the disease,” says Elisabet Stener-Victorin of the Karolinska Institute in Sweden. It also highlights the need to include diverse ancestries in genetic studies of PCOS, says Zhao.
Ultimately, researchers identified drugs that could correct the pathways affected by the identified variants. Some of these are already used to treat PCOS, such as clomiphene, which stimulates the release of eggs from the ovary, a process disrupted by the disease. The team also found that betaine – sometimes used to treat homocystinuria, a genetic condition that can cause eye and skeletal problems – could also benefit people with PCOS. Studies in mice with induced PCOS-like symptoms could explore this treatment option, Zhao says.
“Today, treatment is symptom-driven; there is no drug that can cure PCOS,” says Stener-Victorin. Common therapies include the birth control pill to regulate periods, the type 2 diabetes medication clomiphene or metformin, which may improve fertility. But no treatment is effective for everyone. “Identifying groups of genes that influence PCOS risk can really help us direct and implement more targeted treatment for these women,” she says.
Topics:
