Genetic associations of metabolic factors and therapeutic drug targets with polycystic ovary syndrome

作者：Changlong Zhang, Yuxuan Li, Yang Wang, Shourui Hu, Yue Liu, Xiaofan Liang, Zi‐Jiang Chen, Yuqing Zhang, Han Zhao · 发表于：Journal of Advanced Research · 年份：2024 · DOI：10.1016/j.jare.2024.10.038 · 被引用次数：12 · 研究领域：Ovarian function and disorders、Genetic Associations and Epidemiology、Growth Hormone and Insulin-like Growth Factors

INTRODUCTION: Polycystic ovary syndrome (PCOS) is frequently accompanied with metabolic dysfunctions, yet the causal relationships between metabolic factors and PCOS remain to be conclusively established and etiology-based therapies are lacking. OBJECTIVES: To comprehensively identify the metabolic causal factors and potential drug targets for PCOS. METHODS: This genetic association study was conducted using bidirectional two-sample Mendelian Randomization (MR), multivariable MR (MVMR) and drug-target MR. Considering metabolic sexual dimorphism, female-specific genome-wide association studies (GWASs) for metabolic factors were obtained. To ensure the robustness of the findings, an additional independent PCOS GWAS dataset was utilized for replication. RESULTS: The PCOS cohort included 10,074 PCOS cases (mean age 28 to 45 years) and 103,164 controls (mean age 27 to 60 years) of European ancestry. All participants were female. Employing two-sample MR analysis, we found that genetically proxied body mass index (BMI) (OR = 3.40 [95 % CI, 2.65-4.36]), triglyceride (TG) (OR = 1.54 [95 % CI, 1.17-2.04]), low-density lipoprotein cholesterol (LDL-c) (OR = 1.37 [95 % CI, 1.07-1.76]), and type 2 diabetes (T2D) (OR = 1.24 [95 % CI, 1.09-1.41]) were significantly associated with an increased risk of PCOS, whereas genetically predicted high-density lipoprotein cholesterol (HDL-c) (OR = 0.61 [95 % CI, 0.47-0.80]) decreased the odds of PCOS. Stepwise MVMR established a hierarchy of interactio...