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 Clin

Posted May 5,2019 in General Medicine.

Dr.Cristina Topola
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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 theJournal of Clinical Endocrinology and Metabolism.

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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 dont know what causes it, the treatments are all symptomatic and its very frustrating that we dont have a cure.

Andrea Dunaif, Lead Author

Now, researchers in New York and Chicago have identified a common variation in a gene calledDENND1Athat may play an important role in the development of polycystic ovary syndrome.

DENND1Ais 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 ofDENND1Aand 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 thatDENND1Aplays 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 ofDENND1Ain ovarian androgen biosynthesis, which is an important biologic pathway that is interrupted in cases of polycystic ovary syndrome.

This previous study found thatDENND1Aencoded two transcripts,DENND1A.V1andDENND1A.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 studys 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 toIFLScience, 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 were 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


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