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A new study has provided the first direct evidence that inherited DNA variants can cause the hormonal abnormalities characteristic of polycystic ovary syndrome (PCOS). Using gene regulatory mapping and CRISPR-based tools in human cell models, researchers identified specific variants in the DENND1A gene that increase testosterone production – the most consistent hormonal change observed in women with PCOS.

Genetic regulation tied to hormone production

PCOS affects 10–15% of women of reproductive age worldwide and is the most common cause of ovulatory infertility. It is associated with long-term risks of type 2 diabetes, obesity and other cardiometabolic disorders. While PCOS is known to be a complex genetic condition, pinpointing the genetic variants responsible for its core hormonal features has been a challenge.

This study is the first to demonstrate how inherited DNA changes can directly increase testosterone production. Earlier studies had only associated broad regions of the genome with PCOS, but the new approach allowed researchers to identify specific gene regulatory elements that affect hormone levels in relevant human cells.

Two-step genetic screening approach

To conduct the study, researchers focused on 14 genomic regions previously linked to PCOS in genome-wide association studies (GWAS). They screened thousands of DNA sequences from these regions for gene regulatory activity in hormone-producing cells using a high-throughput assay. This allowed them to identify functional elements – or “regulatory switches” – associated with PCOS.

CRISPR-based epigenome editing

A technique that allows scientists to modify gene activity without changing the DNA sequence.

Genome-wide association studies (GWAS)

Studies that scan the genome for small differences in DNA – called variants – that are more common in individuals with a particular condition.

They then applied CRISPR-based epigenome editing to activate these regulatory elements in two human cell models: one that produces testosterone (adrenal steroid-producing cells) and another that produces estradiol (ovarian granulosa cells). This method modulates gene activity without changing the DNA sequence.

DENND1A activation drives testosterone production

Among the regions studied, variants in the regulatory sequences of the DENND1A gene were shown to increase its expression and promote testosterone production in the adrenal cell model. In total, researchers identified over 1,000 gene regulatory elements across the 14 loci, including in genes like FSHB and GATA4. However, DENND1A was the only one shown to directly influence hormone output in the model system.

DENND1A

A gene associated with PCOS that, when overexpressed, has been linked to increased production of testosterone in hormone-producing cells.

This result provides a mechanistic link between genetic variation and the most consistent endocrine abnormality seen in PCOS – elevated testosterone levels.

Clinical relevance

For clinicians, the findings offer a molecular explanation for a core feature of PCOS. While previous research had associated the DENND1A region with PCOS, this study establishes that specific variants can functionally increase testosterone in human cells. Such mechanistic insights could guide future research toward therapeutic interventions that target the gene’s regulatory control.

Patient implications

The study reinforces the understanding that PCOS is partly driven by inherited DNA variation. Elevated testosterone in women with PCOS contributes to hallmark symptoms including menstrual irregularities, infertility and increased male-pattern hair growth. By identifying gene switches that cause this hormonal imbalance, the research lays the groundwork for treatments aimed at modifying gene regulation to normalize hormone levels.

Future directions

This work is a proof of concept. Researchers studied only 14 of the now approximately 30 PCOS-linked genomic regions. They plan to apply the same two-step approach to additional loci using more genetically diverse populations. The goal is to build a fuller map of the gene regulation pathways disrupted in PCOS.

Reference: Sankaranarayanan L, Brewer KJ, Morrow S, et al. Gene regulatory activity associated with polycystic ovary syndrome revealed DENND1A-dependent testosterone production. Nat Commun. 2025;16(1):7697. doi: 10.1038/s41467-025-62884-7

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