Large-scale study identifies shared genetic architecture for polycystic ovary syndrome diagnosis

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In the largest genetic analysis of polycystic ovary syndrome (PCOS) performed to date, an international consortium, including researchers at the Icahn School of Medicine at Mount Sinai, conducted a whole genome association study to identify common genetic architecture for different diagnostic criteria used to define the syndrome. The results are available online in the December 19 issue of the journal PLOS Genetics.

PCOS is among the most common endocrine disorders in reproductive-age women; it is a leading cause of infertility and type 2 diabetes. The origin of PCOS is unknown. It is currently diagnosed based on different sets of clinical criteria, which is controversial and possibly less accurate.

The researchers explored the genetic basis of PCOS by conducting a meta-analysis of seven whole-genome association studies involving more than 10,000 women with PCOS and 100,000 controls of European ancestry. These studies included 2,540 patients diagnosed using the National Institutes of Health criteria (high testosterone and irregular menstrual cycles); 2,669 patients using the Rotterdam criteria (high egg production); and 5,184 self-reported cases from the personal genetics company 23andMe.

With the benefit of this sample size, researchers were able to identify 14 gene variants that were associated with PCOS, including three that were identified for the first time. All the new genetic variants plausibly linked to both metabolic and reproductive features of PCOS.

“One of our most important findings is simply that all the fighting that goes on in the field over which diagnostic criteria to use is unnecessary,” said Andrea Dunaif, MD, Chief of the Hilda and J. Lester Gabrilove Division of Endocrinology, Diabetes, and Bone Disease at the Icahn School of Medicine at Mount Sinai, and one of the senior authors of the study. “We can be pretty broad in our diagnosis with the criteria we have and be assured we are going to find the same genetic forms of PCOS.”

Additional analyses provided further insight into the biology of PCOS. There was evidence that the genetic pathways identified in this study are also linked to other conditions, including obesity, type 2 diabetes, menopause, and depression. In addition, the researchers found for the first time that there are some links to male pattern baldness. The association between PCOS and male-pattern balding is particularly intriguing since it is the first genetic evidence for shared disease biology in men. The genetic link with depression supports epidemiologic studies that have found an increased risk for depression in women with PCOS.

“This study also indicates the enormous power of genome-wide association studies to provide insight into the disease. For the first time, we’re making real progress on understanding the causal pathways leading to PCOS and the diseases that are genetically related to it,” added Dr. Dunaif, an international authority on the disease.

Ultimately, Dr. Dunaif hopes that these biologic insights will enable the development of novel therapies for PCOS.

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This work was developed through the international collaboration among 50 institutions. The International PCOS Consortium received funding from a number of organizations, including the National Institutes of Health, European Union’s Horizon 2020 research and innovation program and National Institute of Health Research Biomedical Researcher Centre.

About the Mount Sinai Health System

The Mount Sinai Health System is New York City’s largest integrated delivery system encompassing (with the addition of South Nassau Communities Hospital) eight hospital campuses, a leading medical school, and a vast network of ambulatory practices throughout the greater New York region. Mount Sinai’s vision is to produce the safest care, the highest quality, the highest satisfaction, the best access and the best value of any health system in the nation. The Health System includes approximately 7,480 primary and specialty care physicians; 11 joint-venture ambulatory surgery centers; more than 410 ambulatory practices throughout the five boroughs of New York City, Westchester, Long Island, and Florida; and 31 affiliated community health centers. The Icahn School of Medicine is one of three medical schools that have earned distinction by multiple indicators: ranked in the top 20 by U.S. News & World Report‘s “Best Medical Schools”, aligned with a U.S. News & World Report‘s “Honor Roll” Hospital, No. 12 in the nation for National Institutes of Health funding, and among the top 10 most innovative research institutions as ranked by the journal Nature in its Nature Innovation Index. This reflects a special level of excellence in education, clinical practice, and research. The Mount Sinai Hospital is ranked No. 18 on U.S. News & World Report‘s “Honor Roll” of top U.S. hospitals; it is one of the nation’s top 20 hospitals in Cardiology/Heart Surgery, Gastroenterology/GI Surgery, Geriatrics, Nephrology, and Neurology/Neurosurgery, and in the top 50 in six other specialties in the 2018-2019 “Best Hospitals” issue. Mount Sinai’s Kravis Children’s Hospital also is ranked nationally in five out of ten pediatric specialties by U.S. News & World Report. The New York Eye and Ear Infirmary of Mount Sinai is ranked 11th nationally for Ophthalmology and 44th for Ear, Nose, and Throat. Mount Sinai Beth Israel, Mount Sinai St. Luke’s, Mount Sinai West, and South Nassau Communities Hospital are ranked regionally.

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