Half of all women with PCOS share a rare gene variant

Scientists have discovered a common genetic variant in half of all women with polycystic ovary syndrome (PCOS). The genetic alteration causes high levels of testosterone and may be the cause of the condition. This is the first study of its kind and has been published in the Journal of Clinical Endocrinology and Metabolism.

PCOS is exceptionally common and it is poorly understood. Many women need to see as many as four physicians before they get a diagnosis.Shidlovski | Shutterstock

PCOS is ‘exceptionally common’

Polycystic ovary syndrome affects approximately five to 15 percent of premenopausal women worldwide, depending on the diagnostic criteria, and is the main cause of infertility and type 2 diabetes in women.

It is a common condition that is thought to develop due an imbalance of reproductive hormones that negatively affects how eggs develop in the ovaries. However, the exact cause has not yet been identified.

It is widely believed that genetics along with high levels of androgens (male sex hormones including testosterone) in women and high levels of insulin causes polycystic ovary syndrome.

The condition can cause missed or irregular periods that may lead to infertility or cysts on the ovaries. Symptoms of polycystic ovary syndrome include hirsutism, a condition that sees women develop too much hair on their faces, chin, or on parts of the body where only men tend to have hair. Conversely, thinning hair and male-pattern baldness can also be experienced, along with acne, weight gain, and skin tags.

Whatever the reason, PCOS is exceptionally common and it is poorly understood. Many women need to see as many as four physicians before they get a diagnosis. Because we don’t know what causes it, the treatments are all symptomatic and it’s very frustrating that we don’t have a cure.”

Andrea Dunaif, Lead Author

Now, researchers in New York and Chicago have identified a common variation in a gene called DENND1A that may play an important role in the development of polycystic ovary syndrome.

DENND1A is a gene that is involved in the production of male hormones, and was found to be an “important regulator of human ovarian androgen biosynthesis.”

While the study explains that PCOS is “highly heritable” only a “small proportion of this heritability can be accounted for by the common genetic susceptibility variants identified to date.”

‘New insights’

Using whole-genome sequencing techniques, lead researcher Andrea Dunaif, from the Icahn School of Medicine at Mount Sinai in New York, found significant associations between a rare variant of DENND1A and “reproductive and metabolic traits in PCOS families.”

The study included 261 people from 62 families with PCOS. The families included were Caucasian and had European ancestry, and the women were aged 14 to 63 years old.

The researchers say that the findings “provide additional evidence that DENND1A plays a central role in PCOS and suggest that rare noncoding variants contribute to disease pathogenesis.”

These results are in addition to evidence produced by previous studies that investigated the role of DENND1A in ovarian androgen biosynthesis, which is an important biologic pathway that is interrupted in cases of polycystic ovary syndrome.

This previous study found that DENND1A encoded two transcripts, DENND1A.V1 and DENND1A.V2, the latter of which was found in ovarian cells and was linked to increased androgen production.

Andrea Dunaif expanded on the significance of her study’s results, saying:

Our findings provide important new insights into the mechanisms by which genetic variation causes PCOS. The rare genetic variants we found may be much better for predicting the condition than the common variants. Targeting pathways regulated by this gene could lead to new therapies for the condition.”

Andrea Dunaif

A new screening tool

Speaking to IFLScience, Andrea Dunaif said that this research may be able to identify high-risk individuals earlier than is currently possible.

“The hope would be that with genetic testing we may be able to identify high-risk people and start measures early.

“When we understand the genetic pathways that are involved, we can develop drugs to target them. It may be that the gene variants that we’re discovering, which are mainly in the parts of DENND1A, regulate the amount of it that is produced in tissues and maybe some of the structure.

“If we understand that, then we may be able to come up with ways to alter the increase in DENND1A activity that happens in PCOS and treat the disease itself and even cure a number of patients.”

The study notes that other genes were also among the “top gene associations”, but were not significant genome-wide. These genes included C9orf3, HMGA2, ZBTB16, TOX3, and THADA.

We hope our results will help uncover some of the involved hereditary mechanisms and ultimately teach us more about the molecular drivers of the disorder.”

Dr. Geoffrey Hayes, Co-author

Lois Zoppi

Written by

Lois Zoppi

Lois is a freelance copywriter based in the UK. She graduated from the University of Sussex with a BA in Media Practice, having specialized in screenwriting. She maintains a focus on anxiety disorders and depression and aims to explore other areas of mental health including dissociative disorders such as maladaptive daydreaming.


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