Genetic associations with PCOS

A new study, published in the American Journal of Obstetrics and Gynecology, suggests that polycystic ovary syndrome (PCOS) may be linked to the epidermal growth factor receptor (EGFR) and the Hippo pathways. These results could play an important role in future risk screening and disease management for patients with the condition.

The study used data from three health records-linked biobanks, the Geisinger MyCode Community Health Initiative, the electronic Medical Records and Genomics Network (eMERGE) and BioVU at Vanderbilt University, to identify and analyze novel, genome-wide variations in patients with PCOS.

Although there are different sets of criteria for diagnosing PCOS, the authors deemed the Rotterdam criteria as more inclusive and thus more sensitive than the others in practice, namely that of the National Institutes of Health and the Androgen Excess and PCOS.

Data from women aged 18 to 45 were analyzed. Patients that met two of the three Rotterdam criteria were included in the sample. Control samples were from patients that did not meet any of the three criteria and whose age exceeded the study’s median diagnosis of 38.

An individual genome-wide association analysis was then performed to look for associations with each criterion in a phenotype algorithm that the researchers developed based on the Rotterdam criteria.

With 2,995 qualifying patients and 53,599 population controls, the authors identified one novel genome-wide significant variant, rs17186366 (SOD2), and two loci with suggestive association to PCOS: rs113168128 (ERBB4) and rs144248326 (WWTR1). They found that rs17186366 (SOD2) was associated with polycystic ovaries and hyperandrogenism, while rs11316812 (ERBB4) and rs144248326 (WWTR1) were mainly associated with oligomenorrhea or infertility. They also validated a previously reported association between PCOS and DENND1A1.

Moderate associations were found between the top three variants and behavioral disorders, including depression, which may suggest a genetic predisposition between PCOS and mental disorders.

The findings confirmed the association between PCOS and ERBB4 and identified a novel association with SOD2 and WWTR1. Because the YAP1 gene has been previously associated with PCOS, the ERBB4-YAP1-WWTR1 network suggests that EGFR and the Hippo pathway play significant roles in the etiology of PCOS. The authors noted, however, that “the algorithm might not fully reflect the Rotterdam criteria because it assumes the same evaluation and coding practices at each healthcare system, which is not often true in real-world practice. Their findings, they believe, could help address the lack of focused risk screening and disease management for PCOS in clinical practice and result in more accurate diagnoses.