Dissecting the shared genetic architecture between anti-Müllerian hormone and age at menopause based on genome-wide association study

Abstract

BackgroundWhile the phenotypic association between anti-Müllerian hormone (AMH) and age at menopause has been widely studied, the role of AMH in predicting the age at menopause is currently controversial, and the genetic architecture or causal relationships underlying these two traits is not well understood. AimWe aimed to explore the shared genetic architecture between AMH and age at menopause, to identify shared pleiotropic loci and genes, and to investigate causal association and potential causal mediators. Study DesignUsing summary statistics from publicly available genome-wide association studies on AMH (N=7,049) and age at menopause (N=201,323) in Europeans, we investigated the global genetic architecture between AMH and age at menopause through linkage disequilibrium score regression. We employed pleiotropic analysis under composite null hypothesis (PLACO), Functional Mapping and Annotation of Genetic Associations (FUMA), Multimarker analysis of GenoMic annotation (MAGMA), and colocalization analysis to identify loci and genes with pleiotropic effects. Tissue enrichment analysis based on GTEx data was conducted using the Linkage Disequilibrium Score for the specific expression of genes analysis (LDSC-SEG). Functional genes that were shared were additionally identified through summary data-based Mendelian randomization (SMR). The relationship between AMH and age at menopause was examined through two-sample Mendelian randomization (MR), and potential mediators were further explored using colocalization and metabolite-mediated analysis. ResultsA positive genetic association (correlation coefficient = 0.88, P = 1.33 × 10-5) was observed between AMH and age at menopause. By using PLACO and FUMA, 42 significant pleiotropic loci were identified that were associated with AMH and age at menopause, and ten of these (rs10734411, rs61913600, rs2277339, rs75770066, rs28416520, rs9796, rs11668344, rs403727, rs6011452, and rs62237617) had colocalized loci. Additionally, 245 significant pleiotropic genes were identified by MAGMA. Genetic associations between AMH and age at menopause were markedly concentrated in various tissues including whole blood, brain, heart, liver, muscle, pancreas, and kidneys. Further, SMR analysis revealed nine genes that may have a causative effect on both AMH and age at menopause. A potential causal effect of age at menopause on AMH was suggested by two-sample MR analysis, with very-low-density lipoprotein identified as a potential mediator. ConclusionsOur study revealed a shared genetic architecture between AMH 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 AMH 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.