Novel Genetic Risk and Metabolic Signatures of Insulin Signaling and Androgenesis in the Anovulation of Polycystic Ovary Syndrome
Xiaoke Wu,
Chi Chiu Wang,
Yijuan Cao,
Jian Li,
Zhiqiang Li,
Hongli Ma,
Jingshu Gao,
Hui Chang,
Duojia Zhang,
Jing Cong,
Yu Wang,
Qi Wu,
Xiaoxiao Han,
Pui Wah Jacqueline Chung,
Yiran Li,
Xu Zheng,
Lingxi Chen,
Lin Zeng,
Astrid Borchert,
Hartmut Kuhn,
Zi-Jiang Chen,
Ernest Hung Yu Ng,
Elisabet Stener-Victorin,
Heping Zhang,
Richard S. Legro,
Ben Willem J. Mol,
Yongyong Shi
Affiliations
Xiaoke Wu
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China; Department of Reproductive Medicine, Heilongjiang Provincial Hospital, Harbin Institute of Technology, Harbin 150030, China; Corresponding authors.
Chi Chiu Wang
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China; Reproduction and Development Laboratory, Li Ka Shing Institute of Health Sciences & Chinese University of Hong Kong–Sichuan University Joint Laboratory in Reproductive Medicine, The Chinese University of Hong Kong, Hong Kong 999077, China
Yijuan Cao
Center for Reproductive Medicine, Xuzhou Central Hospital, Xuzhou 221009, China
Jian Li
Department of Obstetrics and Gynecology, The Affiliated Hospital of Gui Zhou Medical University, Guiyang 550004, China
Zhiqiang Li
Biomedical Sciences Institute, The Affiliated Hospital of Qingdao University, Qingdao 266000, China; Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China
Hongli Ma
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Jingshu Gao
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Hui Chang
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Duojia Zhang
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Jing Cong
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Yu Wang
The First Affiliated Hospital, Heilongjiang University of Chinese Medicine, Harbin 150040, China
Qi Wu
Department of Obstetrics and Gynecology, Obstetrics and Gynecology Hospital, Fudan University, Shanghai 200001, China
Xiaoxiao Han
Clinical and Translational Research Center of Shanghai First Maternity and Infant Hospital, Shanghai 200001, China; Shanghai Key Laboratory of Signaling and Disease Research, Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200001, China
Pui Wah Jacqueline Chung
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
Yiran Li
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
Xu Zheng
Department of Obstetrics and Gynaecology, The Chinese University of Hong Kong, Hong Kong 999077, China
Lingxi Chen
Department of Computer Sciences, City University of Hong Kong, Hong Kong 999077, China
Lin Zeng
Shanghai NewCore Biotechnology Co., Ltd., Shanghai 200240, China
Astrid Borchert
Institute of Biochemistry, Charité—University Medicine Berlin, Berlin 10117, Germany
Hartmut Kuhn
Institute of Biochemistry, Charité—University Medicine Berlin, Berlin 10117, Germany
Zi-Jiang Chen
Center for Reproductive Medicine, Shandong University, Jinan 250001, China
Ernest Hung Yu Ng
Department of Obstetrics and Gynaecology, The University of Hong Kong, Hong Kong 999077, China
Elisabet Stener-Victorin
Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm 17177, Sweden
Heping Zhang
Department of Biostatistics, Yale School of Public Health, New Haven, CT 06520, USA
Richard S. Legro
Department of Obstetrics and Gynecology, Pennsylvania State University, Hershey, PA 17033, USA
Ben Willem J. Mol
Department of Obstetrics and Gynaecology, Monash University, Monash Medical Centre, Clayton, VIC 3168, Australia; Aberdeen Centre for Women's Health Research, School of Medicine, Medical Sciences and Nutrition, University of Aberdeen, Aberdeen AB25 2ZD, UK
Yongyong Shi
Key Laboratory for the Genetics of Developmental and Neuropsychiatric Disorders, Bio-X Institutes, Ministry of Education, Shanghai Jiao Tong University, Shanghai 200030, China; Corresponding authors.
Ovulation induction is a first-line medical treatment for infertility in polycystic ovary syndrome (PCOS). Poor ovulation responses are assumed to be due to insulin resistance and hyperandrogenism. In a prospective cohort (PCOSAct) of 1000 infertile patients with PCOS, whole-exome plus targeted single-nucleotide polymorphism (SNP) sequencing and comprehensive metabolomic profiling were conducted. Significant genome-wide common variants and rare mutations associated with anovulation were identified, and a prediction model was built using machine learning. Common variants in zinc-finger protein 438 gene (ZNF438) indexed by rs2994652 (p = 2.47 × 10–8) and a rare functional mutation in REC114 (rs182542888, p = 5.79 × 10–6) were significantly associated with failure of ovulation induction. Women carrying the A allele of rs2994652 and REC114 p.Val101Leu (rs182542888) had lower ovulation (odds ratio (OR) = 1.96, 95% confidence interval (95%CI) = 1.55–2.49; OR = 11.52, 95%CI = 3.08–43.05, respectively) and prolonged time to ovulation (mean = 56.7 versus (vs) 49.0 days, p < 0.001; 78.1 vs 68.6 days, p = 0.014, respectively). L-phenylalanine was found to be increased and correlated with the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) index (r = 0.22, p = 0.050) and fasting glucose (r = 0.33, p = 0.003) for rs2994652, while arachidonic acid metabolism was found to be decreased and associated with increased anti-Müllerian hormone (AMH; r = –0.51, p = 0.01) and total testosterone (TT; r = –0.71, p = 0.02) for rs182542888. A combined model of genetic variants, metabolites, and clinical features increased the prediction of ovulation (area under the curve (AUC) = 76.7%). Common variants in ZNF438 and rare functional mutations in REC114, associated with phenylalanine and arachidonic acid metabolites, contributed to the failure of infertility treatment in women with PCOS.
