The Genetics of Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in reproductive aged women. Its health threatening consequences include a very high rate of type 2 diabetes, impaired glucose tolerance and metabolic syndrome out of proportion to controls matched for body mass index.  In addition, obesity and other cardiovascular risk factors are more prevalent in women with PCOS compared to controls. Twin studies and family studies suggest a genetic basis for this disorder, and the pattern of inheritance is consistent with that of a complex disease. We are using genome-wide association studies to examine the genetics of PCOS.  Our goal is to map the phenotypes of PCOS onto genotypes to further our understanding of the etiology of PCOS and improve treatment modalities in women with PCOS. In addition, we are determining whether the underlying genetic architecture determines the response to metformin treatment.

To date, we have replicated variants associated with risk for PCOS in Han Chinese women. We are currently analyzing the function of a variant located in an intron of DENND1A. In addition, a variant in the gene THADA was replicated in a meta-analysis of women with PCOS of European ethnicity. A variant at a different locus in THADA also confers risk for diabetes. However, there is otherwise little overlap in variants associated with risk for PCOS and for diabetes. Therefore, the discovery of additional loci associated with PCOS risk may provide new insight into the risk factors for type 2 diabetes.


1. Welt CK, Carmina E. Lifecycle of polycystic ovary syndrome (PCOS): from in utero to menopause. 2013;98:4629-4638. PMCID:PMC3849665 [Available on 2014/12/12.2. Saxena R, Welt CK. Polycystic ovary syndrome is not associated with genetic variants that mark risk for type 2 diabetes. ACTA Diabetol. 2013;50:451-457. PMCID: PMC3679224.3. Welt CK*, Styrkarsdottir U*, Ehrmann DA, Thorleifsson G, Arason G, Gudmundsson JA, Ober C, Rosenfield RL, Saxena R, Thorsteinsdottir U, Crowley WF, Stefansson K. Variants in DENND1A are associated with polycystic ovary syndrome in women of European ancestry. J Clin Endocrinol  Metab. 2012;97:E1342-1347. *These authors contributed equally. PMCID:PMC322076

4. Pau C, Saxena R, Welt CK. Evaluating reported candidate gene associations with polycystic ovary syndrome. Fertil Steril. 2013 May;99(6):1774-8.PMCID:PMC37225865. Pau CT, Keefe C, Duran J, Welt CK. Metformin Improves Glucose Effectiveness, Not Insulin Sensitivity: Predicting Treatment Response in Women with Polycystic Ovary Syndrome in an Open-Label, Interventional Study. J Clin Endocrinol Metab. 2014 May;99(5):1870-8. PMCID:PMC4010712 [Available on 2015/5/1]

6. Keefe CC, Goldman MM, Zhang K, Clarke N, Reitz RE, Welt CK.Simultaneous measurement of thirteen steroid hormones in women with polycystic ovary syndrome and control women using liquid chromatography-tandem mass spectrometry. PLoS One. 2014 Apr 8;9(4):e93805. PMCID:PMC3979722