Gonadotropin Alterations Implicated in Polycystic Ovary Syndrome

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Researchers have discovered several new genetic susceptibility regions for polycystic ovary syndrome, according to a study published in Nature Communications.

A team from Northwestern University Feinberg School of Medicine in Chicago collected DNA from nearly 9,000 women and genotyped nearly 700,000 genetic markers from each individual as part of a genome-wide association study to gain new insights into the underlying biology of the disorder. The NUgene Project, a genomic biobank sponsored by the Center for Genetic Medicine at Northwestern in partnership with Northwestern Medicine, provided many of the control samples.

The researchers were able to identify two new genetic susceptibility regions that appear to be unique to European women with polycystic ovary syndrome (PCOS), as well as one region also present in Chinese women with PCOS.

One of these new regions contained the gene for the pituitary hormone gonadotropin, follicle stimulating hormone (FSH), providing evidence that disruption in this pathway, which regulates ovarian function, plays an essential role in the development of PCOS.

"Identifying the genes associated with PCOS give us clues about the biological pathways that cause the disorder," said Andrea E. Dunaif, MD, Charles F. Kettering Professor of Endocrinology and Metabolism, and senior author of the study. "Understanding these pathways can lead to new treatments and disease prevention approaches."

As a result of previous research from Dunaif's lab, PCOS also is associated with insulin resistance and is now recognized as a leading risk factor for type-2 diabetes in young women. Her group has been at the forefront of genetic studies of PCOS and has shown that male relatives and the children of affected women are at increased risk type 2 diabetes and reproductive problems.

Currently, there are no FDA-approved drugs for PCOS. Clinicians can manage symptoms and improve fertility in patients but a cure remains out of reach as long as the cause of the disorder remains unknown.

"Large-scale genetic analyses that became possible after the mapping of the human genome allow us to investigate the entire genome for disease-causing DNA variants. This information will be critical for the development of effective treatments for PCOS and for genetic testing to identify at-risk girls before the onset of symptoms," Dunaif said.

The Northwestern study complements a recent genome-wide association study of Chinese women that identified 11 PCOS susceptibility regions of the genome. The regions include the genes for the receptors for the gonadotropins,
luteinizing hormone (LH) and FSH. LH and FSH acting through these receptors regulate the production of ovarian hormones, such as estradiol and testosterone, as well as the maturation and ovulation of the egg.

Taken together with the Northwestern study, finding of the gene for FSH hormone itself, these analyses implicate genes regulating gonadotropins and their actions in causing PCOS.

"For a number of years, researchers had been thinking that it was testosterone produced by the ovary that was a major problem in PCOS, but our study did not find signals for genes regulating testosterone," Dunaif said. "In contrast, we did find a signal for the FSH gene, which is produced in the pituitary gland at the base of the brain."

The current study suggests that FSH, either how it acts on the ovary or how it is secreted, plays an important role in the development of PCOS and represents a new way of thinking about the biology of the disorder.

"The next step in this research is to use the genetic variations in the genes that confer increased risk for PCOS and build models to investigate the how the biologic pathways implicated are disrupted functionally," said M. Geoffrey Hayes, the lead author of the study who specializes in statistical genetics at Feinberg.

"One of the three gene regions identified in our study in Europeans was also found in Chinese suggesting that there may be some shared genetic susceptibility to PCOS in Europeans and Chinese, who diverged evolutionarily more than 40,000 years ago. We plan to DNA sequence the regions that we found in common with the Chinese."

A partnership is underway between Northwestern University and Shandong University in China to further advance this work. More genome-wide association studies of PCOS are needed in other racial and ethnic groups, according to the researchers. A study is planned to investigate the genomes of women of African ancestry with the disorder.

Gonadotropin Alterations Implicated in Polycystic Ovary Syndrome
A genome-wide association study provided new insights into the underlying biology of polycystic ovary disorder.

Polycystic ovary syndrome (PCOS) is a common, highly heritable complex disorder of unknown aetiology characterized by hyperandrogenism, chronic anovulation and defects in glucose homeostasis. Increased luteinizing hormone relative to follicle-stimulating hormone secretion, insulin resistance and developmental exposure to androgens are hypothesized to play a causal role in PCOS.

Here we map common genetic susceptibility loci in European ancestry women for the National Institutes of Health PCOS phenotype, which confers the highest risk for metabolic morbidities, as well as reproductive hormone levels.

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