Project II: Epigenetic and Expression Analysis of PCOS

While PCOS has a strong familial component and has been shown to be highly heritable (h2=0.8), traditional genetic studies conducted by our laboratory and others have identified only a limited number of reproducible PCOS susceptibility genetic loci. It is clear from current genetic studies of PCOS and other complex phenotypes that common genetic variation does not explain the bulk of the observed heritability. Therefore, it has been proposed that rare variants contribute complex traits like PCOS. Project I will test this hypothesis. However, an additional (and not mutually exclusive) explanation for this observed deficit is that the observed heritability in complex phenotypes is due to epigenetic rather than genomic variation. Epigenetic changes are heritable changes in gene expression or cellular phenotype that occur in the absence of changes to the DNA sequence. Variation in DNA methylation patterns is one major form of epigenetic variation and can be captured on a genome-wide level. The observation that prenatal androgen administration can produce complete phenocopies of PCOS in animal models further supports a role for such epigenetic mechanisms in PCOS. However, to date there have been no genome-wide analyses of differential DNA methylation carried out in either animal or human models. It is our hypothesis that a significant component of the heritability observed in PCOS is due to 1) epigenetic changes including variation in methylation pattern, 2) that these changes in methylation patterns correlate with changes in expression patterns, and 3) that these changes in methylation are due to either specific changes in the DNA or environmental factors including the in utero environment (i.e. prenatal androgen exposure). We propose to test these hypotheses by measuring the effect of differentially methylated regions or DMRs on PCOS status in PCOS target tissues (muscle, visceral fat, subcutaneous (SQ) fat, and liver) of obese women with and without PCOS, the impact of DMRs on gene expression in these samples, and whether these DMRs are due to epigenetic changes including those caused by environmental factors like the intrauterine environment (i.e. prenatal androgen exposure) or due to genetic variation. Finally, we will test our strongest signals, in marmoset tissues. These novel and innovative studies will provide insight into the role of epigenetic variation in PCOS, a complex phenotype with major metabolic and reproductive health consequences but is resistant to traditional genetic approaches.


Principal Investigator

Margrit Urbanek, PhD

Associate Professor of Medicine, Division of Endocrinology, Metabolism and Molecular Medicine, Feinberg School of Medicine, Northwestern University


Kjersti Aagaard, MD, PhD
Associate Professor of Obstetrics and Gynecology- Maternal-Fetal Medicine, Baylor College of Medicine

Andrea Dunaif, MD
Charles F. Kettering Professor of Endocrinology & Metabolism and Vice Chair for Research, Department of Medicine, Feinberg School of Medicine, Northwestern University

Eric S. Hungness, MD

Assistant Professor of Surgery, Feinberg School of Medicine, Northwestern University

Alexander P. Nagle, MD
Associate Professor of Surgery, Feinberg School of Medicine, Northwestern University