In the largest genetic study of polycystic ovary syndrome (PCOS) to date, researchers have pinpointed 94 variants that influence the condition's risk, including 73 newly discovered ones. The analysis of over 440,000 women's genomes could pave the way for more targeted treatments. PCOS affects up to one in five women, causing fertility issues and hormonal imbalances.
Polycystic ovary syndrome (PCOS) disrupts ovarian function, leading to irregular periods, elevated male sex hormones like testosterone, and clusters of immature eggs resembling cysts. Affecting up to 20% of women, it often results in fertility problems. While the exact cause remains unknown, prior research linked about 70% of risk to genetics, with only 25 variants previously identified, explaining roughly 10% of cases.
To address this, Shigang Zhao at Shandong University in Jinan, China, and colleagues conducted the biggest genetic analysis yet, examining genomes from more than 440,000 women across China and Europe—25,000 diagnosed with PCOS. They identified 94 variants associated with PCOS risk, 73 of which were novel. One key variant affects the gene for mitochondrial ribosomal protein S22, which supports mitochondrial function—the cell's energy producers. "While prior studies have linked PCOS to dysfunctional mitochondria, this is the first look at how genetics may underly this," says Zhao.
Another variant influences sex hormone-binding globulin, a protein often low in PCOS patients that regulates hormone activity. Many variants impact granulosa cells in the ovaries, which produce oestrogen and progesterone and aid egg development, reinforcing genetics' role in hormonal disruptions.
The variants account for 27% of risk variation in Europeans and 34% in Chinese participants, highlighting the importance of diverse ancestries, per Zhao. "This study is important because it’s expanding our understanding of the genetic component of the disease," says Elisabet Stener-Victorin at the Karolinska Institute in Sweden.
The team also suggested drugs targeting affected pathways, including existing PCOS treatment clomifene, which aids egg release, and betaine, used for homocystinuria. Mouse studies could test betaine further. Current PCOS therapies, like the contraceptive pill or metformin, manage symptoms but lack a cure. "Identifying clusters of genes that influence PCOS risk can really help us to direct and do more targeted treatment," Stener-Victorin adds.