Polycystic ovary syndrome (PCOS) affects 10% of women, but it is often misdiagnosed or missed entirely by physicians. Now, researchers said identified the genetic underpinnings of the syndrome, including 3 new loci, a causal link to depression, and a male phenotype for PCOS.1
PCOS is characterized by irregular menstrual cycles, an increased number of eggs arrested in development, and excessive facial hair or acne. Women may also suffer from weight gain, type 2 diabetes, anxiety, and depression. Women with PCOS often have difficulty conceiving, and may have metabolic issues, including insulin resistance and trouble regulating blood sugar. A recent research letter in JAMA Oncology linked PCOS
to an increased risk of cancer.2
However, despite the fact that PCOS is the most common endocrine disorder in women of reproductive age, physicians have different ways of diagnosing PCOS, depending on their specialty.
“Patients often go from doctor to doctor before they get a diagnosis, because medical professionals may not be familiar with PCOS and providers from dermatology to obstetrics and gynecology to endocrinology may diagnose PCOS differently,” Corrine Welt, MD, interim chief of the division of endocrinology and metabolism at the University of Utah Health, said in a statement
. The results appeared last week in the journal PLOS Genetics.
There are 2 different sets of diagnostic criteria. One, from the National Institutes of Health (NIH), requires the presence of clinical and/or biochemical high testosterone and irregular menstrual cycles. The Rotterdam criteria includes the presence of polycystic ovarian morphology and requires at least 2 of 3 traits to be present, resulting in 4 phenotypes.
In this study, done by the International PCOS Consortium, researchers confirmed 11 previously reported loci and found 3 new ones (near PLGRKT
). Some of the data came from women who were customers of 23andMe who opted into the research. The authors said that group, identified by self-report, had similar risks to the group where the diagnosis was clinically confirmed.
In the study, the researchers separated the PCOS patients into 3 groups based on diagnosis.
Patients diagnosed using the NIH criteria (2540 cases and 15,020 controls) accounted for about 70% of PCOS cases. Patients diagnosed using the Rotterdam criteria (high egg production; 2669 cases and 17,035 controls) accounted for up to 20% of PCOS cases.
The genetic similarities between cases diagnosed based on the 2 criteria have been largely unknown. The researchers also examined self-identified PCOS cases from 23andMe (5184 cases and 82,759 controls).
They identified 14 gene variants that were associated with PCOS, including 3 that were identified for the first time. Only 1 of these 14 genetic variants differed significantly in its association by diagnostic criteria.
The researchers next examined the associations of these 14 gene variants with specific PCOS related traits in 3 additional studies with a combined total of more than 10,000 PCOS patients and found 4 variants associated with high testosterone, 8 variants associated with high egg production, and 9 variants associated with infertility, with 3 variants associated with all 3 traits.
There were also genetic correlations with obesity, fasting insulin, type 2 diabetes, lipid levels and coronary artery disease, indicating shared genetic architecture between metabolic traits and PCOS.
Other variants were found to have a causal link to menopause timing, depression and male-pattern balding.
Felix Day, PhD, senior research associate in Growth and Development at the Medical Research Council Epidemiology Unit at the University of Cambridge, England, and contributing author, said the next steps are to further characterize the causes of PCOS.
1. Day F, Karaderi T, Jones MR, et al. Large-scale genomic-wide meta analysis of polycystic ovary syndrome suggests shared genetic architecture for different diagnosis criteria. [published online December 19, 2018]. PLoS Genet. doi: 10.1371/journal.pgen.1007813
2. Yin W, Falconer H, Yin L, Xu L, Ye W. Association between polycystic ovary syndrome and cancer risk. [published online November 29, 2018]. JAMA Oncol. doi:10.1001/jamaoncol.2018.5188.