Zeynep Erdoğan-Yildirim - Final Dissertation Defense - HUGEN PhD Candidate

Department of Human Genetics Doctoral Candidate, Zeynep Erdoğan-Yildirim, defends her dissertation on “Examining Polycystic Ovary Syndrome and its Relevant Biomarkers in Samoan Women via Machine Learning-Based Phenotyping and Genome-Wide Association Studies” 

ADVISOR: Ryan L. Minster, PhD, MSIS

Committee Members:

• Daniel E. Weeks, PhD
• Mylynda B. Massart, MD, PhD
• Evelyn O. Talbott, DrPH, MPH

ABSTRACT:

Polycystic ovary syndrome (PCOS) is the most common reproductive endocrinological disorder in women. It is highly heritable disorder with multifactorial and polygenic etiology. Genome-wide studies in various populations have revealed several significant loci. Yet, the underlying mechanisms remain to be explored. Because studies in genetically isolated populations are valuable resource to gain novel biological insights, I investigated the underlying genetic factors of PCOS and relevant biomarkers in Samoan women from the Soifua Manuia Study.

The first aim required phenotyping of study participants since no clinical diagnosis of PCOS was available. Taking advantage of supervised machine learning methods, several models were trained, tested and validated on European cohorts with known outcomes. The best performing model was ranger, a random forest algorithm, which I used to classify individuals into high-risk PCOS cases and low-risk PCOS controls.

In the second aim, I explored genetic factors associated with high-risk PCOS on 584 women from two independent Samoan samples via genome-wide association meta-analysis. Five loci showed suggestive association: TBX3, ERCC6L2, KRT4, C9orf163/SEC16A and CA8. Although none of the loci have known direct causal role in PCOS, some of the loci were either involved in gonadogenesis, were differentially expressed in adipose tissue of women with PCOS or were closely located to known PCOS loci.

The third aim interrogated genetic factors regulating the levels of cardinal biomarkers of PCOS – total testosterone (TT), free androgen index (FAI), sex hormone-binding globulin (SHBG) and anti-Müllerian hormone (AMH) – in a meta-analysis of 1102 Samoan women. I observed that rs1220069967 in ABO was genome-wide significant for both TT and FAI and is in high linkage disequilibrium with the previously identified rs494242 in ABO that is associated with TT levels in Europeans. Additional suggestive association signals were found for TT (N = 11), FAI (N = 12), SHBG (N = 7) and AMH (N = 14).

This preliminary study provides promising initial findings regarding the genetic underpinnings of PCOS and its biomarkers in Samoans. They need to be validated through additional genetic and functional follow-up studies. These findings expand our knowledge and may help improve public health through the discovery of better screening and diagnostic markers as well as therapeutic targets for PCOS.