A Polygenic and Phenotypic Risk Prediction for Polycystic Ovary Syndrome Evaluated by Phenome-Wide Association Studies

Yoonjung Yoonie Joo, Ky'Era Actkins, Jennifer A Pacheco, Anna O Basile, Robert Carroll, David R Crosslin, Felix Day, Joshua C Denny, Digna R Velez Edwards, Hakon Hakonarson, John B Harley, Scott J Hebbring, Kevin Ho, Gail P Jarvik, Michelle Jones, Tugce Karaderi, Frank D Mentch, Cindy Meun, Bahram Namjou, Sarah PendergrassMarylyn D Ritchie, Ian B Stanaway, Margrit Urbanek, Theresa L Walunas, Maureen Smith, Rex L Chisholm, Abel N Kho, Lea Davis, M Geoffrey Hayes*, International PCOS Consortium, Jenny A. Visser

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

36 Citations (Scopus)
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CONTEXT: As many as 75% of patients with polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice.

OBJECTIVE: Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment.

DESIGN, PATIENTS, AND METHODS: Leveraging the electronic health records (EHRs) of 124 852 individuals, we developed a PCOS risk prediction algorithm by combining polygenic risk scores (PRS) with PCOS component phenotypes into a polygenic and phenotypic risk score (PPRS). We evaluated its predictive capability across different ancestries and perform a PRS-based phenome-wide association study (PheWAS) to assess the phenomic expression of the heightened risk of PCOS.

RESULTS: The integrated polygenic prediction improved the average performance (pseudo-R2) for PCOS detection by 0.228 (61.5-fold), 0.224 (58.8-fold), 0.211 (57.0-fold) over the null model across European, African, and multi-ancestry participants respectively. The subsequent PRS-powered PheWAS identified a high level of shared biology between PCOS and a range of metabolic and endocrine outcomes, especially with obesity and diabetes: "morbid obesity", "type 2 diabetes", "hypercholesterolemia", "disorders of lipid metabolism", "hypertension", and "sleep apnea" reaching phenome-wide significance.

CONCLUSIONS: Our study has expanded the methodological utility of PRS in patient stratification and risk prediction, especially in a multifactorial condition like PCOS, across different genetic origins. By utilizing the individual genome-phenome data available from the EHR, our approach also demonstrates that polygenic prediction by PRS can provide valuable opportunities to discover the pleiotropic phenomic network associated with PCOS pathogenesis.

Original languageEnglish
Pages (from-to)1918-1936
Number of pages19
JournalThe Journal of clinical endocrinology and metabolism
Issue number6
Publication statusPublished - 1 Jun 2020

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© Endocrine Society 2020. All rights reserved. For permissions, please e-mail: [email protected].

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