The Genetics of Polycystic Ovary Syndrome

Principal Investigator: Corrine Welt
Keywords: polycystic ovary syndrome , irregular menstrual cycles , acne , hair growth , hyperandrogenism , polycystic ovaries , women's health Department: Endocrinology/Diabetes Researc
IRB Number: 00076659 Co Investigator:  
Specialty: Endocrinology and Metabolism, Women and Children's Health
Sub Specialties:
Recruitment Status: Recruiting

Contact Information

Corrine Welt

Brief Summary

Polycystic Ovary Syndrome (PCOS) is one of the most common endocrine disorders in women. Its marked phenotypic variability, broad range of associated conditions, and potential risk to a woman’s health over her lifecycle remain a clinical investigational, genetic, and therapeutic challenge. We plan to address many of these long-term clinical research obstacles by delineating the genetic basis of PCOS. We will use a genome-wide association study approach and will also incorporate a family-based approach to identify the genes associated with PCOS. 

Specific Aim 1: To identify DNA variants that are associated with risk for PCOS using a genome-wide association approach.

Hypothesis 1: Genome-wide significant PCOS risk variants will be identified using a genome-wide association approach. 

Hypothesis 2: PCOS risk variants in U.S. women will be replicated in additional populations of U.S. women and women of Greek ethnicity. 

Hypothesis 3: Meta-analysis with additional populations will replicate risk variants identified in the discovery population along with additional risk variants that reach genome-wide significance.

Specific Aim 2: To identify DNA variants associated with PCOS using a family-based approach.

Hypothesis 4: Whole exome or genome sequencing in families with multiple affected women will identify novel PCOS risk variants.

Hypothesis 5: PCOS risk variants identified in families will be replicated in additional populations of U.S. women and women of Greek ethnicity. 

Specific Aim 3: To determine the association between genotype and phenotype in women with PCOS.

Hypothesis 6: PCOS subjects carrying associated PCOS risk variants will demonstrate an additive increase in androgen levels, ovarian volume and follicle number.

Hypothesis 7: PCOS subjects carrying PCOS risk variants will demonstrate an additive adverse effect on adiposity, insulin sensitivity, inflammatory markers and metabolic features, independent of higher androgen levels.

Hypothesis 8: Male and postmenopausal carriers of PCOS risk variants will have a phenotype defined by assessing androgens, anthropomorphic measures and metabolic parameters.

Hypothesis 9: The genotype/phenotype associations found in U.S. women will be replicated in additional populations of U.S. women and Icelandic women.

Inclusion Criteria

In this proposal, 4 groups of subjects will be studied.  A group of 500 PCOS probands and their family members and 500 control subjects age and sex matched to the PCOS probands and family members will be recruited. The total number of subjects will be 1000.

Inclusion Criteria-PCOS Probands:  1)  Aged 18 yrs or above 2) Oligomenorrhea or amenorrhea (<9 menses/yr); 3) clinical and/or biochemical evidence of hyperandrogenemia; 4) normal TSH and prolactin <25 ng/mL. 

Inclusion Criteria-Male and Female Relatives:  1) Aged at 18 yrs or above. 

Inclusion Criteria-Control Subjects: ) Aged at 18 yrs or above; 2) Regular menstrual cycles 21-35 days or history of regular menstrual cycles in the past if menopausal for female controls; 3) no clinical or biochemical evidence of hyperandrogenemism for female controls; 4) normal TSH and prolactin <25 ng/mL; 5) on no hormonal, steroidal or insulin sensitizing medication for at least 3 months; 5) healthy.  


Cohorts Already Recruited and Transferred from Massachusetts General Hospital

In addition to subjects recruited specifically in the current study, subject samples from previously approved studies will be subsumed under this IRB protocol. A description of the cohorts follows.

1. “The Genetics of PCOS” is a study that has been ongoing at Massachusetts General Hospital since 2002. The protocol is identical to that in the current study. The PI has permission to transfer all of the samples and identified patient data to the University of Utah (see attached Letter of Collaboration). The original cohort consists of PCOS Cases (n=730), controls (n=820) and family members (n=31), total n=1581. IRB 2002P001924.

2. Additional samples were acquired through the IRB protocol entitled “Determining the Familial Contribution in Subsets of Polycystic Ovary Syndrome”: Cases (n=141), controls (n=10) and family members (n=128). These subjects had a blood draw for DNA and completed a questionnaire. IRB 1999P007675.

3. Replication Cohort – Greece: PCOS Cases (n=1151) and controls (n=359). These DNA samples are a deidentified Greek cohort sent in collaboration from Dr. Neoklis Georgopoulos. IRB 2002P001924.

4. Replication Cohort - Reproductive Medicine Network: PCOS Cases (n=230). The DNA is from the PPCOSI study and is deidentified (31). IRB 2002P001924.

5. Replication Cohort - PCOS Cases (n=600) and controls (n=1858) in a deidentified Boston cohort. The cohort was originally identified through the Research Patient Database at Partners Healthcare. The medical record numbers of cases and controls were submitted to the Partners Biobank. Discarded whole blood and serum was collected by the Biobank service and sample identifiers removed before giving to the PI. These samples are still in collection and will be sent, deidentified, to Dr. Welt. IRB 2012P002417.

6. PCOS Cases and family members serum samples deidentified Icelandic subjects. DNA is not available on these subjects. IRB 2002P001924.

Exclusion Criteria

Exclusion Criteria-PCOS Probands: Subjects will not have 1) late onset congenital adrenal hyperplasia as defined by a fasting 17OH progesterone level <200 ng/mL or a cortrosyn stimulated 17 OH progesterone level <500 ng/mL.

Exclusion Criteria-Male and Female Relatives and Controls: Contraindication to blood drawing or severe chronic illness.