Identifying genetic factors of polycystic ovary syndrome in women with epilepsy: a whole-genome sequencing study

Introduction: Women with epilepsy (WWE) are more likely to develop reproductive endocrine disorders, especially polycystic ovary syndrome (PCOS). This study aimed to explore the genetic factors of PCOS in WWE in hope of improving individual precision diagnosis and treatment. Methods: WWE registered at West China Hospital between January 2021 and October 2021 were enrolled in this study. Demographic and epilepsy-related characteristics were recorded and blood samples were collected for hormones, glucose metabolism testing and whole-genome sequencing. Results: After sample sequencing, quality control and variants selection, association analyses were performed. Pathway analysis was performed to identify involved biological pathways. The overall and PCOS 'burden score' of each individual were calculated to count the deleterious variants. A total of 95 WWE was included in this study and 19 patients were diagnosed with PCOS. WWE with PCOS showed a significantly different hormone profiles and a tendency of impaired glucose metabolism. The mostly associated genes were ZFYVE28, COL19A1, SIK3, ANKK1, PPIG, and REPIN1. The top 3 canonical pathways are adipogenesis pathway, Epoxysqualene Biosynthesis Signaling, and Glutamate Degradation Signaling. The most significant common variant was rs11914038 located in gene CELSR1 and rs651748 located in gene ZBTB16. In HGC prioritizations, ITGA9, PNPLA2, and DAB2 are the top 3 genes having the shortest distance to known PCOS genes. Conclusion: Genetic factors involved in the abnormal regulation of glucose and insulin metabolism are likely to be associated with the comorbidity of PCOS in WWE. Interventions targeting these processes should be given more priority in clinical practice.

Automated summary

This study aimed to explore the genetic factors of polycystic ovary syndrome (PCOS) in women with epilepsy (WWE). The findings showed significant differences in hormone profiles and impaired glucose metabolism in WWE with PCOS. The genes most associated with PCOS were ZFYVE28, COL19A1, SIK3, ANKK1, PPIG, and REPIN1. The adipogenesis pathway, Epoxysqualene Biosynthesis Signaling, and Glutamate Degradation Signaling were the top three canonical pathways. The study also identified common variants located in CELSR1 and ZBTB16 genes. Genetic factors related to glucose and insulin metabolism regulation may be associated with the comorbidity of PCOS in WWE.