PCOS is a common endocrine disorder affecting women of childbearing age, manifesting as menstrual irregularity, infertility and metabolic disorders, including insulin resistance and obesity. The estimated prevalence of PCOS based on the NIH diagnostic criteria ranges between 6-12% in populations in the United States and many other countries, including the United Kingdom, Australia, Spain, Greece and Iran^1-7. Significant morbidity is associated with PCOS due to infertility, an increased risk of type 2 diabetes and other complications secondary to obesity, including lipid disorders, sleep apnea and possibly an increased risk for endometrial carcinoma⁸.

The treatment of PCOS involves a multidisciplinary approach. Weight loss for the subset of patients with obesity is considered the most cost-effective intervention, usually leading to normalization of menses and reestablishment of fertility. Metformin and clomiphene are used for ovulation induction, with variable response in terms of ovulation. Overall, only about 50% of women with PCOS are able to conceive after treatment with clomiphene. Oral contraceptives are recommended for endometrial protection (prevention of endometrial hyperplasia, a risk factor for endometrial carcinoma). Androgen excess (hirsutism and acne) are treated with spironolactone (a diuretic), usually in combination with an oral contraceptive with minimal androgenicity. Type 2 diabetes is managed with lifestyle modification, metformin, oral hypoglycaemic agents, exenatide, and in some cases, with insulin. PCOS is a difficult disorder to treat and patients usually have an incomplete response to the treatments described above. Because the etiology of this condition is unknown, an optimal and effective therapeutic approach to the disease has not been achieved. Women with PCOS face the social stigma of infertility and obesity and struggle with aesthetic problems related to hirsutism.

PCOS is a major public health problem considering its devastating clinical effects and how common it is. Our study will be the first whole genome sequencing project to explore causal mutations and causal allelic variants in the context of a well-defined phenotype of PCOS.