A polygenic and phenotypic risk prediction for Polycystic Ovary Syndrome evaluated by Phenome-wide association studies
Yoonjung Yoonie Joo,
Jennifer A Pacheco,
Anna O. Basile,
David R Crosslin,
Joshua C Denny,
Digna R. Velez Edwards,
John B. Harley,
Scott J Hebbring,
Gail P Jarvik,
Frank D Mentch,
Marylyn DeRiggi Ritchie,
Ian B. Stanaway,
Theresa L. Walunas,
Rex L Chisholm,
International PCOS Consortium,
Abel N Kho,
M. Geoffrey Hayes
Posted 24 Jul 2019
bioRxiv DOI: 10.1101/714113 (published DOI: 10.1210/clinem/dgz326)
Posted 24 Jul 2019
Purpose: As many as 75% of patients with Polycystic ovary syndrome (PCOS) are estimated to be unidentified in clinical practice. Utilizing polygenic risk prediction, we aim to identify the phenome-wide comorbidity patterns characteristic of PCOS to improve accurate diagnosis and preventive treatment. Methods and Findings: 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. 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.
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