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.

促排卵是治疗多囊卵巢综合征 (PCOS) 不孕症的一线药物。排卵反应不良被认为是由于胰岛素抵抗和高雄激素血症。在 1000 名 PCOS 不育患者的前瞻性队列 (PCOSAct) 中，进行了全外显子组加靶向单核苷酸多态性 (SNP) 测序和全面的代谢组学分析。确定了与无排卵相关的重要全基因组常见变异和罕见突变，并使用机器学习建立了预测模型。由 rs2994652 ( p  = 2.47 × 10 ^–8 ) 索引的锌指蛋白 438 基因 ( ZNF438 ) 的常见变异和REC114中的罕见功能突变(rs182542888, p = 5.79 × 10 ^–6 ) 与促排卵失败显着相关。携带 rs2994652 和REC114 p.Val101Leu (rs182542888) A 等位基因的女性排卵率较低（比值比 (OR) = 1.96，95% 置信区间 (95%CI) = 1.55–2.49；OR = 11.52，95%CI = 3.08 –43.05，分别）和延长的排卵时间（平均值 = 56.7 与 (vs) 49.0 天，p  < 0.001；78.1 与 68.6 天，p  = 0.014，分别）。L-苯丙氨酸被发现增加并与胰岛素抵抗稳态模型评估 (HOMA-IR) 指数 ( r  = 0.22, p  = 0.050) 和空腹血糖 ( r  = 0.33, p = 0.003) 对于 rs2994652，同时发现花生四烯酸代谢减少并与抗苗勒管激素（AMH；r  = –0.51，p  = 0.01）和总睾酮（TT；r  = –0.71，p  = 0.02）增加有关对于 rs182542888。遗传变异、代谢物和临床特征的组合模型增加了排卵的预测（曲线下面积 (AUC) = 76.7%）。ZNF438的常见变异和REC114的罕见功能突变，与苯丙氨酸和花生四烯酸代谢物相关，导致 PCOS 女性不育治疗失败。