PCOS is a highly heritable (-78%) non-Mendelian disorder. Nevertheless, the common PCOS genetic susceptibility variants mapped by us and by others do not account for the observed heritability of PCOS. This so-called missing heritability has also been observed for other common, highly heritable complex traits such as T2D, height and body mass index (BMI). An explanation for this paradox that is gaining increasing experimental support is that the observed heritability is due to infrequent or rare variants with larger biological effects, in addition to the common variants already identified. Detection of these rare variants is now becoming feasible with the advent of high-throughput Next Generation DNA Sequencing methodologies. It is our overarching hypothesis that rare variants will account for a considerable proportion ofthe missing heritability of PCOS. There will be two Aims: 1) To test the hypothesis that rare genetic variants account for much of the deficit in heritability in women with PCOS. Whole genome sequencing will be performed to identify genetic variants in PCOS families with a proband and three additional affected sisters, in probands from the phenotypic extreme ofthe PCOS population and in women who remain reproductively normal despite morbid obesity. Variants that may have functional consequences that are concordant in the four affected sibs will be genotyped in the remaining family members in these families to identify those that co- segregate with PCOS. These variants, as well as novel/rare variants that are found at elevated frequency in the extreme phenotypes group(s), will be genotyped in the larger set of families with multiple affected sisters, and in the larger case-control population. 2) To test the hypothesis that rare variants identified in Aim 1 are associated with sex-specific metabolic phenotypes in PCOS. Genotype-phenotype associations will be investigated to investigate whether variants mapped with the PCOS reproductive phenotype also have a metabolic phenotype. Rare variants will be investigated in male first-degree relatives to determine if the associated metabolic phenotypes are sex-specific.

Public Health Relevance

PCOS affects 7% of premenopausal women. It is a leading risk factor for type 2 diabetes in affected women and their male as well as female relatives making PCOS a major public health concern. The genetic variants we identify should provide considerable insight into the biological pathways that are disrupted in PCOS. This information should identify novel therapeutic targets and permit better disease prediction.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Specialized Center (P50)
Project #
3P50HD044405-15S1
Application #
9527917
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Taymans, Susan
Project Start
2002-09-27
Project End
2018-06-30
Budget Start
2016-07-01
Budget End
2017-06-30
Support Year
15
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Northwestern University at Chicago
Department
Type
DUNS #
005436803
City
Chicago
State
IL
Country
United States
Zip Code
60611
Abbott, David H; Vepraskas, Sarah H; Horton, Teresa H et al. (2018) Accelerated Episodic Luteinizing Hormone Release Accompanies Blunted Progesterone Regulation in PCOS-like Female Rhesus Monkeys (Macaca Mulatta) Exposed to Testosterone during Early-to-Mid Gestation. Neuroendocrinology 107:133-146
Kraynak, Marissa; Colman, Ricki J; Flowers, Matthew T et al. (2018) Ovarian estradiol supports sexual behavior but not energy homeostasis in female marmoset monkeys. Int J Obes (Lond) :
Gorsic, Lidija K; Kosova, Gulum; Werstein, Brian et al. (2017) Pathogenic Anti-Müllerian Hormone Variants in Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:2862-2872
Abbott, D H; Rayome, B H; Dumesic, D A et al. (2017) Clustering of PCOS-like traits in naturally hyperandrogenic female rhesus monkeys. Hum Reprod 32:923-936
Sam, Susan; Vellanki, Priyathama; Yalamanchi, Sudha K et al. (2017) Exaggerated glucagon responses to hypoglycemia in women with polycystic ovary syndrome. Metabolism 71:125-131
True, Cadence; Abbott, David H; Roberts Jr, Charles T et al. (2017) Sex Differences in Androgen Regulation of Metabolism in Nonhuman Primates. Adv Exp Med Biol 1043:559-574
Kraynak, Marissa; Flowers, Matthew T; Shapiro, Robert A et al. (2017) Extraovarian gonadotropin negative feedback revealed by aromatase inhibition in female marmoset monkeys. Am J Physiol Endocrinol Metab 313:E507-E514
Gibson-Helm, Melanie; Teede, Helena; Dunaif, Andrea et al. (2017) Delayed Diagnosis and a Lack of Information Associated With Dissatisfaction in Women With Polycystic Ovary Syndrome. J Clin Endocrinol Metab 102:604-612
Dunaif, Andrea (2016) Perspectives in Polycystic Ovary Syndrome: From Hair to Eternity. J Clin Endocrinol Metab 101:759-68
Abbott, David H; Levine, Jon E; Dumesic, Daniel A (2016) Translational Insight Into Polycystic Ovary Syndrome (PCOS) From Female Monkeys with PCOS-like Traits. Curr Pharm Des 22:5625-5633

Showing the most recent 10 out of 123 publications