Shao Huijing, Xu Chang, Wang Haoran, Lu Nan, Gu Hang, Zhang Caihong, Li Lirong, Sun Qianqian, Guan Rui, Xuan Beibei
Department of Obstetrics and Gynecology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, China.
Department of Obstetrics and Gynecology, The First Affiliated Hospital of Naval Medical University, No. 168, Changhai Road, Yangpu District, Shanghai, 200433, China.
Reprod Biol Endocrinol. 2025 May 14;23(1):71. doi: 10.1186/s12958-025-01406-y.
While the phenotypic link between body mass index (BMI) and some female reproductive disorders is well established, the genetic architecture and causal relationships have not been systematically studied. We aimed to create an atlas of the shared genetic associations of BMI and 16 female reproductive disorders and to identify their common risk loci, biological pathways, and potential mechanisms.
We assessed the genetic correlations between BMI and 16 reproductive disorders using summary data from large-scale genome-wide association studies. Cross-trait pleiotropic analysis identified shared loci and genes, while functional annotation and tissue-specific analysis revealed relevant biological pathways and tissues. Multi-trait colocalization analysis examined the role of hormones and metabolites in these traits. Additionally, bidirectional Mendelian randomization (MR) analysis was employed to assess causal relationships between BMI and reproductive outcomes. We also conducted summary data-based MR (SMR) analysis to identify potential drug targets.
Our results revealed a significant genetic correlation between BMI and eight female reproductive diseases. Furthermore, we identified 50 shared pleiotropic loci between BMI and these traits, with 21 of them showing significant colocalization, suggesting a complex shared genetic architecture across the genome. In addition, the top biological pathways and tissues enriched with these pleiotropic loci were associated with RNA metabolism, macromolecule biosynthesis, type B pancreatic cell apoptosis, various brain regions, and the pituitary. Moreover, multi-trait colocalization indicated that insulin, lipid metabolites, glucose, glycine, and glutamine mediate shared mechanisms between BMI, gestational diabetes mellitus (GDM), and endometrial cancer. MR analysis suggested BMI may cause several reproductive diseases, with only GDM affecting BMI reversely. Finally, SMR analysis revealed EIF2S2P3 and MCM6, which may have a causative effect on both BMI & GDM and BMI & gestational hypertension.
Our results suggest a significant genetic link between BMI and eight female reproductive diseases, highlighting a shared and causal genetic basis. Reducing BMI in women may serve as an effective strategy to lower the risk of female reproductive disorders. The identified pleiotropic loci, genes, and shared pathways could provide new therapeutic targets for both obesity and reproductive diseases, along with their comorbidities.
Not applicable.
虽然体重指数（BMI）与某些女性生殖系统疾病之间的表型联系已得到充分证实，但基因结构和因果关系尚未得到系统研究。我们旨在创建一个BMI与16种女性生殖系统疾病共享基因关联图谱，并确定它们的共同风险位点、生物学途径和潜在机制。
我们使用大规模全基因组关联研究的汇总数据评估了BMI与16种生殖系统疾病之间的遗传相关性。跨性状多效性分析确定了共享位点和基因，而功能注释和组织特异性分析揭示了相关的生物学途径和组织。多性状共定位分析研究了激素和代谢物在这些性状中的作用。此外，采用双向孟德尔随机化（MR）分析来评估BMI与生殖结局之间的因果关系。我们还进行了基于汇总数据的MR（SMR）分析以确定潜在的药物靶点。
我们的结果显示BMI与8种女性生殖系统疾病之间存在显著的遗传相关性。此外，我们确定了BMI与这些性状之间的50个共享多效性位点，其中21个显示出显著的共定位，表明整个基因组存在复杂的共享基因结构。此外，富含这些多效性位点的主要生物学途径和组织与RNA代谢、大分子生物合成、B型胰腺细胞凋亡、各个脑区和垂体有关。此外，多性状共定位表明胰岛素、脂质代谢物、葡萄糖、甘氨酸和谷氨酰胺介导了BMI、妊娠期糖尿病（GDM）和子宫内膜癌之间的共享机制。MR分析表明BMI可能导致几种生殖系统疾病，只有GDM会反向影响BMI。最后，SMR分析揭示了EIF2S2P3和MCM6，它们可能对BMI与GDM以及BMI与妊娠期高血压都有因果影响。
我们的结果表明BMI与8种女性生殖系统疾病之间存在显著的遗传联系，突出了共同的因果遗传基础。降低女性的BMI可能是降低女性生殖系统疾病风险的有效策略。确定的多效性位点、基因和共享途径可以为肥胖症和生殖系统疾病及其合并症提供新的治疗靶点。
不适用。
