Mount Sinai-Duke University study identifies DNA variants that increase testosterone production in PCOS patients

(Press-News.org) Journal: Nature Communications

Title: Gene Regulatory Activity Associated with Polycystic Ovary Syndrome Reveals DENND1A-Dependant Testosterone Production

Authors: Andrea Dunaif, MD, Chief of the Division of Endocrinology, Diabetes and Bone Disease for the Mount Sinai Health System and the Lillian and Henry M. Stratton Professor of Molecular Medicine at the Icahn School of Medicine at Mount Sinai

Bottom line: Increased testosterone levels are a consistent hormonal abnormality in women with polycystic ovary syndrome (PCOS). This study identified specific DNA variants in the gene DENND1A, which increase testosterone production in PCOS. Using human PCOS cell models, researchers demonstrated that activating these DNA switches turns on DENND1A and drives testosterone production. This provides the first direct evidence that inherited DNA changes can cause the hormone imbalance at the core of PCOS.

Why this study is unique: This is the first time that specific inherited DNA variants for PCOS have been shown to alter hormone production in a human PCOS cell model. While earlier studies mapped broad “regions of interest” in the genome, none had identified the precise functional switches that change hormone biology.

Why the study is important: PCOS is one of the most common conditions in reproductive-age women, affecting 10 to 15 percent of this population globally. It is a complex genetic disorder that reflects the interaction of multiple genes with the environment. PCOS is the leading cause of infertility related to disrupted ovulation and is now recognized as a major cardiometabolic disorder across the lifespan, strongly linked to type 2 diabetes and obesity. Elevated testosterone levels are its most consistent hormonal feature. Understanding how inherited DNA changes lead to increased testosterone levels could open the door to new therapies for PCOS.

How the research was conducted: Nearly 10 years ago, researchers selected the 14 genomic regions that had been associated with PCOS at that time. Using a high-throughput reporter assay, they scanned thousands of DNA sequences in those regions for regulatory activity, identifying the “regulatory switches” that control the expression of genes in hormone-producing cells. They then used genome-wide association studies (GWAS) data to determine which of these regulatory elements were associated with PCOS. This two-step design enabled researchers to focus solely on PCOS-associated regulatory regions, thereby significantly reducing the number of women with PCOS who needed to be studied.

Finally, researchers applied clustered interspaced short palindromic repeats (CRISPR)-based epigenome editing—a precise method that can turn DNA switches on or off without altering the underlying code—to activate regulatory regions in human cell models: one that produces testosterone (in adrenal steroid-producing cells) and another that produces estradiol (in ovarian granulosa cells). Researchers identified DENND1A regulatory regions that increased DENND1A expression and testosterone production in a PCOS testosterone-producing cell model, proving a direct mechanistic link between genetic variants and the hormonal features of PCOS.

Results: Researchers identified more than 1,000 regulatory DNA elements across 14 PCOS loci in hormone-producing cell models. Several regions, including FSHB, GATA4, and DENND1A, contained regulatory variants associated with PCOS. In the PCOS testosterone-producing cell model, activating the DENND1A regulatory DNA increased its expression and testosterone production.

What this study means for doctors: For clinicians, this study identifies the genetic variants in DENND1A that underlie the fundamental hormonal abnormality of PCOS, elevated testosterone levels. Previous studies had shown that a gene region containing DENND1A was associated with PCOS, but there had been no direct evidence that specific variants in the regulatory region of this gene increased testosterone production in a human PCOS cell model. This type of mechanistic insight could eventually lead to treatments aimed at lowering testosterone production at its genetic source.

What this study means for patients: For patients, this study shows that PCOS is driven in part by inherited DNA variants that directly increase testosterone production. Understanding these mechanisms opens the possibility of therapies that could target the genes or regulatory switches responsible for increased testosterone production in PCOS. High levels of testosterone, a male hormone, cause many symptoms of PCOS, such as increased male-pattern hair growth and disruption of ovulation, leading to irregular menstrual cycles and infertility.

What the next steps are for this work: This is a proof-of-concept study. DENND1A is only one of the 14 regions we studied, and there are now about 30 PCOS loci known. The next step is to apply this two-step approach to the remaining regions, including larger and more diverse populations, to build a more comprehensive picture of the disrupted pathways in PCOS.

Quotes: “For the first time, we have shown how specific inherited DNA variants in PCOS change gene activity and increase testosterone production. That moves us from statistical association to biological mechanism. Our innovative approach of first identifying regulatory regions in PCOS susceptibility genes, then determining which of these regions were associated with PCOS, allowed us to focus functional testing on regions with a high likelihood of containing disease-causing variants. Identifying the precise mechanisms by which DNA variation causes complex disorders such as PCOS is one of the major challenges in human genetics. The framework we developed could transform how we study complex disorders beyond PCOS,” Dr. Dunaif said.

About the Mount Sinai Health System

Mount Sinai Health System is one of the largest academic medical systems in the New York metro area, with 48,000 employees working across seven hospitals, more than 400 outpatient practices, more than 600 research and clinical labs, a school of nursing, and a leading school of medicine and graduate education. Mount Sinai advances health for all people, everywhere, by taking on the most complex health care challenges of our time—discovering and applying new scientific learning and knowledge; developing safer, more effective treatments; educating the next generation of medical leaders and innovators; and supporting local communities by delivering high-quality care to all who need it.

Through the integration of its hospitals, labs, and schools, Mount Sinai offers comprehensive health care solutions from birth through geriatrics, leveraging innovative approaches such as artificial intelligence and informatics while keeping patients’ medical and emotional needs at the center of all treatment. The Health System includes approximately 9,000 primary and specialty care physicians and 10 free-standing joint-venture centers throughout the five boroughs of New York City, Westchester, Long Island, and Florida. Hospitals within the System are consistently ranked by Newsweek’s® “The World’s Best Smart Hospitals, Best in State Hospitals, World Best Hospitals and Best Specialty Hospitals” and by U.S. News & World Report's® “Best Hospitals” and “Best Children’s Hospitals.” The Mount Sinai Hospital is on the U.S. News & World Report® “Best Hospitals” Honor Roll for 2025-2026. 

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