Institute of Reproductive & Stem Cell Engineering, Center of Reproductive Health, School of Basic Medical Science, Central South University, Changsha, Hunan, China.
Center of Genetics, Changsha Jiangwan Maternity Hospital, Changsha City, Hunan, China.
Am J Obstet Gynecol. 2024 Dec;231(6):634.e1-634.e11. doi: 10.1016/j.ajog.2024.06.050. Epub 2024 Jul 3.
While the phenotypic association between anti-Müllerian hormoneand age at menopause has been widely studied, the role of anti-Müllerian hormone in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these 2 traits is not well understood.
We aimed to explore the shared genetic architecture between anti-Müllerian hormone and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators.
Using summary statistics from publicly available genome-wide association studies on anti-Müllerian hormone (N=7049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between anti-Müllerian hormone and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis, Functional Mapping and Annotation of Genetic Associations, multimarker analysis of GenoMic annotation, and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on Genotype-Tissue Expression data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis. Functional genes that were shared were additionally identified through summary data-based Mendelian randomization. The relationship between anti-Müllerian hormone and age at menopause was examined through 2-sample Mendelian randomization, and potential mediators were further explored using colocalization and metabolite-mediated analysis.
A positive genetic association (correlation coefficient=0.88, P=1.33×10) was observed between anti-Müllerian hormone and age at menopause. By using pleiotropic analysis under composite null hypothesis and Functional Mapping and Annotation of Genetic Associations, 42 significant pleiotropic loci were identified that were associated with anti-Müllerian hormone and age at menopause, and 10 of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by multimarker analysis of GenoMic annotation. Genetic associations between anti-Müllerian hormone and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, summary data-based Mendelian randomization analysis revealed 9 genes that may have a causative effect on both anti-Müllerian hormone and age at menopause. A potential causal effect of age at menopause on anti-Müllerian hormone was suggested by 2-sample Mendelian randomization analysis, with very-low-density lipoprotein identified as a potential mediator.
Our study revealed a shared genetic architecture between anti-Müllerian hormone and age at menopause, providing a basis for experimental investigations and individual therapies to enhance reproductive outcomes. Furthermore, our findings emphasized that relying solely on anti-Müllerian hormone is not sufficient for accurately predicting the age at menopause, and a combination of other factors needs to be considered. Exploring new therapeutics aimed at delaying at the onset of menopause holds promise, particularly when targeting shared genes based on their shared genetic architecture.
抗苗勒管激素与绝经年龄之间的表型关联已得到广泛研究，但抗苗勒管激素在预测绝经年龄中的作用目前仍存在争议，并且这两个特征的遗传结构或因果关系尚未得到很好的理解。
我们旨在探讨抗苗勒管激素和绝经年龄之间的共享遗传结构，确定共同的多效性位点和基因，并研究因果关系和潜在的因果中介。
利用来自欧洲人群的抗苗勒管激素（N=7049）和绝经年龄（N=201323）的公开全基因组关联研究汇总统计数据，我们通过连锁不平衡评分回归研究抗苗勒管激素和绝经年龄之间的全球遗传结构。我们采用复合无效假设下的多效性分析、遗传关联的功能映射和注释、基于基因组注释的多标记分析以及共定位分析来确定具有多效性效应的位点和基因。使用特定基因表达的连锁不平衡评分进行基于基因型-组织表达数据的组织富集分析。通过基于汇总数据的孟德尔随机化进一步确定共享的功能基因。通过两样本孟德尔随机化研究抗苗勒管激素与绝经年龄之间的关系，并通过共定位和代谢物介导分析进一步探讨潜在的中介物。
抗苗勒管激素和绝经年龄之间存在正遗传关联（相关系数=0.88，P=1.33×10）。通过复合无效假设下的多效性分析和遗传关联的功能映射和注释，确定了 42 个与抗苗勒管激素和绝经年龄相关的显著多效性位点，其中 10 个（rs10734411、rs61913600、rs2277339、rs75770066、rs28416520、rs9796、rs11668344、rs403727、rs6011452 和 rs62237617）具有共定位位点。此外，通过基于基因组注释的多标记分析确定了 245 个显著的多效性基因。抗苗勒管激素与绝经年龄之间的遗传关联主要集中在各种组织中，包括全血、大脑、心脏、肝脏、肌肉、胰腺和肾脏。此外，基于汇总数据的孟德尔随机化分析揭示了 9 个可能对抗苗勒管激素和绝经年龄都具有因果作用的基因。两样本孟德尔随机化分析提示绝经年龄对抗苗勒管激素可能具有潜在的因果作用，极低密度脂蛋白被认为是潜在的中介物。
我们的研究揭示了抗苗勒管激素和绝经年龄之间的共享遗传结构，为实验研究和个体治疗提供了依据，以增强生殖结局。此外，我们的研究结果强调，仅依靠抗苗勒管激素不足以准确预测绝经年龄，需要考虑其他因素。探索旨在延迟绝经开始的新治疗方法具有前景，特别是当根据其共享遗传结构针对共同的基因时。
